SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. LEVEMIR(R) (LEV-uh-mere)(insulin detemir [rDNA origin] injection)solution for subcutaneous injectionRead the Patient Information that comes with LEVEMIR(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 that you know how to manage your diabetes. Ask your healthcare provider, if you have any questions about managing your diabetes.What is LEVEMIR LEVEMIR is man-made long-acting insulin, that is used to control high blood sugar in adults and children with diabetes mellitus.It is not recommended to use LEVEMIR to treat diabetic ketoacidosis. Who should not use LEVEMIRDo not take LEVEMIR if:you are allergic to any of the ingredients in LEVEMIR. See the end of this leaflet for complete list of ingredients in LEVEMIR. What should tell my healthcare provider before taking LEVEMIRBefore you take LEVEMIR, tell your healthcare provider if you: have liver or kidney problemshave any other medical conditions. Some medical conditions can affect your insulin needs and your dose of LEVEMIR. are pregnant or plan to become pregnant. It is not known, if LEVEMIR would harm your unborn baby. Talk to your healthcare provider, if you are pregnant or plan to become pregnant. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant.are breastfeeding or plan to breast-feed. It is not known if LEVEMIR passes into breast milk. You and your healthcare provider should decide if you will take LEVEMIR while you breastfeed.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. LEVEMIR may affect the way other medicines work, and other medicines may affect how LEVEMIR works.Know the medicines you take. Keep list of your medicines with you to show your healthcare provider and pharmacist when you get new medicine. How should take LEVEMIRTake LEVEMIR exactly as your healthcare provider told you to take it.Your healthcare provider will tell you how much LEVEMIR to take and when to take it.Do not make any changes to your dose or type of insulin unless you are told to do so by your healthcare provider.Know your insulin. Make sure you know: the type and strength of insulin prescribed for you.the amount of insulin you take.the best time for you to take your insulin. This may change if you take different type of insulin.Do not dilute or mix LEVEMIR with any other insulin or solution. Your LEVEMIR will not work the right way and you may lose blood sugar control, which can be serious.Do not use LEVEMIR in an insulin pump.Inject LEVEMIR under your skin (subcutaneously) in your upper arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into vein or muscle.Change injection sites within the area you choose with each dose. Do not inject into the exact same spot for each injection.Read the instructions for use that comes with your LEVEMIR. Talk to your healthcare provider if you have any questions. Your healthcare provider should show you how to inject LEVEMIR before you start taking it.Your healthcare provider will decide which type of LEVEMIR to prescribe for you.LEVEMIR comes in: 10 mL vials (small bottles) for use with syringe3 mL LEVEMIR FlexPen(R) Ask your healthcare provider how you should use LEVEMIR. If you take too much LEVEMIR, 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 (lose consciousness).If you pass out you will need help from another person or emergency medical services right away. See What are the possible side effects of LEVEMIR for more information on low blood sugar (hypoglycemia).If you forget to take your dose of LEVEMIR, 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:increased thirstfrequent urinationdrowsinessloss of appetite hard time breathing fruity smell on the breathhigh amounts of sugar and ketones in your urinenausea, vomiting (throwing up) or stomach painDo not share needles, insulin pens or syringes with others.Check 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:illnessstressother medicines you takechange in dietchange in physical activity or exercise What should avoid while taking LEVEMIRAlcohol. Drinking alcohol may affect your blood sugar when you take LEVEMIR.Driving and operating machinery. You may have trouble paying attention 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 for you to drive if you often have:low blood sugar (hypoglycemia)decreased or no warning signs of low blood sugar What are the possible side effects of LEVEMIRLEVEMIR can cause serious side effects, including:Low blood sugar (hypoglycemia). Symptoms of low blood sugar may include:dizziness or lightheadednessshakinesshungerfast heart beattingling in your hands, feet, lips or tongue trouble concentrating or confusionblurred visionslurred speechanxiety or mood changesheadachesweatingVery low blood sugar (hypoglycemia) can cause loss of consciousness (passing out), seizures, and death. Talk to your healthcare provider about how to tell if you have low blood sugar and what to do if this happens while taking LEVEMIR. 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. Your dose of LEVEMIR may need to be changed.Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) the area where you inject your insulin to help prevent these skin changes from happening. Do not inject insulin into areas of skin that have thickening or pits. Serious allergic reactions. LEVEMIR can cause life threatening symptoms. Get medical help right away if you have any of these symptoms of an allergic reaction:a rash all over your bodyitchingshortness of breathtrouble breathing (wheezing)fast heartbeatsweatingfeel faintCommon side effects of LEVEMIR include:Low blood sugar (hypoglycemia). See What are the possible side effects of LEVEMIR for more information on low blood sugar (hypoglycemia).Reactions 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. Weight gain. This can occur with any insulin therapy. Talk to your healthcare provider about how LEVEMIR can affect your weight.Tell your healthcare provider if you have any side effect that bothers you or does not go away.These are not all of the possible side effects from LEVEMIR. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LEVEMIR Unopened LEVEMIR:Keep all unopened LEVEMIR in the refrigerator between 36F to 46F (2C to 8C). Unopened LEVEMIR can be kept until the expiration date on the label if the medicine has been stored in refrigerator.If refrigeration is not possible, you can keep the unopened LEVEMIR at room temperature below 86F (30C). Throw away LEVEMIR 42 days after it is first kept out of the refrigerator.Do not freeze. Do not use LEVEMIR if it has been frozen.Keep unopened LEVEMIR in the carton to protect it from light. LEVEMIR in use:Vials Keep opened vials of LEVEMIR in the refrigerator or at room temperature below 86F (30C) away from direct heat or light. Throw away vial that has always been kept in the refrigerator after 42 days of use, even if there is insulin left in the vial. Throw away vial that has been kept at room temperature 42 days after it is first kept out of the refrigerator, even if there is insulin left in the vial.LEVEMIR FlexPenKeep at room temperature below 86F (30C) for up to 42 days. Do not store LEVEMIR FlexPen that you are using in the refrigerator. Do not store LEVEMIR with the needle attached.Keep LEVEMIR FlexPen away from direct heat or light.Throw away used LEVEMIR FlexPens after 42 days, even if there is insulin left in them.Keep LEVEMIR and all medicines out of the reach of children. General information about LEVEMIRMedicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use LEVEMIR for condition for which it was not prescribed. Do not give LEVEMIR to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about LEVEMIR. If you would like more information about LEVEMIR or diabetes, talk with your healthcare provider. You can ask your healthcare provider for information about LEVEMIR that is written for healthcare professionals. For more information about LEVEMIR, call 1-800-727-6500 or go to www.novonordisk-us.com. What are the ingredients in LEVEMIRActive Ingredient: Insulin detemirInactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium phosphate dehydrate, sodium chloride and water for injection. Hydrochloric acid or sodium hydroxide may be added.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: January 2012 Novo Nordisk(R), LEVEMIR(R), and FlexPen(R) are registered trademarks of Novo Nordisk A/S.LEVEMIR(R) is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 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.(C) 2005-2012 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR(R) contact:Novo Nordisk Inc.100 College Road WestPrinceton, New Jersey 08540www.novonordisk-us.com1-800-727-6500Patient Instructions For Use LEVEMIR (R) 10 mL vial Please read the following Instructions for use carefully before using your LEVEMIR(R) 10 mL vial and each time you get refill. You should read the instructions in this manual even if you have used an insulin 10 mL vial before.How should use the LEVEMIR 10 mL vialUsing the 10 mL vial: 1. Check to make sure that you have the correct type of insulin. This is especially important if you use different types of insulin. 2. Look at the vial and the insulin. The LEVEMIR insulin should be clear and colorless. The tamper-resistant cap should be in place before the first use. If the cap has been removed before your first use of the vial, or if the insulin is cloudy or colored, Do not use the insulin and return it to your pharmacy. 3. Wash your hands with soap and water. 4. If you are using new vial, pull off the tamper-resistant cap. Before each use, wipe the rubber stopper with an alcohol wipe. 5. Do not roll or shake the vial. Shaking the vial right before the dose is drawn into the syringe may cause bubbles or foam. This can cause you to draw up the wrong dose of insulin. The insulin should be used only if it is clear and colorless. 6. Pull back the plunger on your syringe until the black tip reaches the marking for the number of units you will inject. 7. Push the needle through the rubber stopper into the vial. 8. Push the plunger all the way in. This inserts air into the vial. 9. Turn the vial and syringe upside down and slowly pull the plunger back to few units beyond the correct dose that you need. 10. If there are air bubbles, tap the syringe gently with your finger to raise the air bubbles to the top of the needle. Then slowly push the plunger to the correct unit marking for your dose. 11. Check to make sure you have the right dose of LEVEMIR in the syringe. 12. Pull the syringe out of the vial 13. Inject your LEVEMIR right away as instructed by your healthcare provider.How should inject LEVEMIR with syringeIf you clean your injection site with an alcohol swab, let the injection site dry before you inject. Talk with your healthcare provider about how to rotate injection sites and how to give an injection. 1. Pinch your skin between two fingers, push the needle into the skinfold, using dart-like motion and push the plunger to inject the insulin under your skin. The needle will be straight in. 2. Keep the needle under your skin for at least seconds to make sure you have injected all the insulin. After you pull the needle from your skin you may see drop of Levemir at the needle tip. This is normal and has no effect on the dose you just received. 3. If blood appears after you pull the needle from your skin, press the injection site lightly with an alcohol swab. Do not rub the area. 4. After each injection, remove the needlewithout recapping and dispose of it in puncture-resistant container. Used syringes, needles, and lancets should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.Revised: January 2012Novo Nordisk(R) and LEVEMIR(R) are registered trademarks of Novo Nordisk A/S.LEVEMIR(R) is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930, and other patents pending.(C) 2005-2012 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR(R) contact:Novo Nordisk Inc.100 College Road West,Princeton, New Jersey 08540Instructions For UseLEVEMIR(R) FlexPen(R) Please carefully read the following Instructions for use before using your LEVEMIR(R) FlexPen(R) and each time you get refill. You should read the instructions in this manual even if you have used LEVEMIR FlexPen before.LEVEMIR FlexPen is disposable dial-a-dose insulin pen. You can select doses from to 60 units in increments of unit. LEVEMIR FlexPen is designed to be used with NovoFine(R) needles. LEVEMIR FlexPen should not be used by people who are blind or have severe eyesight problems without the help of person who has good eyesight and who is trained to use the LEVEMIR FlexPen the right way. Getting readyMake sure you have the following texts:LEVEMIR FlexPenNovoFine disposable needlesAlcohol swab PREPARING YOUR LEVEMIR FLEXPEN Wash your hands with soap and water. Before you start to prepare your injection, check the label to make sure that you are taking the right type of insulin. This is especially important if you take more than type of insulin. LEVEMIR should look clear and colorless.A. Pull off the pen cap (see diagram A).Wipe the rubber stopper with an alcohol swab.B.Attaching the needleRemove the protective tab from new disposable needle. Attach 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 LEVEMIR FlexPen until you are ready to give your injection.C. Pull off the big outer needle cap (see diagram C).D. Pull off the inner needle cap and throw it away (see diagram D). Always use new needle for each injection to cut down the chance of infection and to prevent blocked needles. Be careful not to bend or damage the needle before use. To reduce the risk of needle sticks, never put the inner needle cap back on the needle. Giving the airshot before each injection Before each injection, small amounts of air may collect in the cartridge during normal use. To avoid injecting air and to ensure you take the right dose of insulin:E. Turn the dose selector to select units (see diagram E).F. Hold your LEVEMIR 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. While you 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 LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500. small air bubble may remain at the needle tip, but it will not be injected. SELECTING YOUR DOSE Check 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. Wipe the skin with an alcohol swab and let the area dry. 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 after the needle is in the skin.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 LEVEMIR at the needle tip. This is normal and has no effect on the dose you just received. If blood appears after you take the needle out of your skin, press the injection site lightly with an alcohol swab. Do not rub the area. After the injectionCarefully remove the needle from the pen after each injection. This helps to prevent infection and leakage of insulin. You can carefully recap the needle with the bigger outer cap to help make it easier to remove the needle. Do not recap the needle with the small inner cap. Recapping with this small part can increase your chances of having needle stick injury. Put the needle 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.K. Put the pen cap on the LEVEMIR FlexPen and store the LEVEMIR FlexPen without the needle attached (see diagram K).The LEVEMIR FlexPen prevents the cartridge from being completely emptied. It can deliver 300 units then you should throw it away in sharps container or some type of hard plastic or metal container with screw top, such as detergent bottle or empty coffee can.FUNCTION CHECKL. If your LEVEMIR FlexPen is not working the right way, follow the steps below:Attach new NovoFine needle.Remove the big outer needle cap and the inner needle cap.Do an airshot as described in Giving the airshot before each injection (see diagram through G).Put the big outer needle cap onto the needle. Do not put on the inner needle cap.Turn the dose selector so the dose indicator window shows 20 units.Hold the LEVEMIR FlexPen so the needle is pointing down.Press the push-button all the way in. The insulin should fill the lower part of the big outer needle cap to the marker (see diagram L). If LEVEMIR FlexPen has released too much or too little insulin, do the function check again. If the same problem happens again, do not use your LEVEMIR 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. If you drop your FlexPen it could get damaged. 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. Soaking or washing the FlexPen could damage it. Do not refill your FlexPen. Remove the needle from the LEVEMIR FlexPen after each injection. This helps to cut down your chance of infection, prevent leakage of insulin. Be careful when handling used needles to avoid needle sticks and transfer of infections. Keep your LEVEMIR FlexPen and needles out of the reach of children. Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and LEVEMIR 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 safety measure, always carry spare insulin delivery device in case your LEVEMIR FlexPen is lost or damaged. Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave it in car or other location where it can get too hot or too cold.Revised: January 2012Novo Nordisk(R) LEVEMIR(R) FlexPen(R) NovoPen(R) and NovoFine(R) are registered trademarks of Novo Nordisk A/S.LEVEMIR(R) is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930, 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.(C) 2005-2012 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR(R) contact:Novo Nordisk Inc.100 College Road West,Princeton, New Jersey 08540. you are allergic to any of the ingredients in LEVEMIR. See the end of this leaflet for complete list of ingredients in LEVEMIR.. have liver or kidney problems. have any other medical conditions. Some medical conditions can affect your insulin needs and your dose of LEVEMIR. are pregnant or plan to become pregnant. It is not known, if LEVEMIR would harm your unborn baby. Talk to your healthcare provider, if you are pregnant or plan to become pregnant. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant.. are breastfeeding or plan to breast-feed. It is not known if LEVEMIR passes into breast milk. You and your healthcare provider should decide if you will take LEVEMIR while you breastfeed.. Take LEVEMIR exactly as your healthcare provider told you to take it.. Your healthcare provider will tell you how much LEVEMIR to take and when to take it.. Do not make any changes to your dose or type of insulin unless you are told to do so by your healthcare provider.. the type and strength of insulin prescribed for you.. the amount of insulin you take.. the best time for you to take your insulin. This may change if you take different type of insulin.. Do not dilute or mix LEVEMIR with any other insulin or solution. Your LEVEMIR will not work the right way and you may lose blood sugar control, which can be serious.. Do not use LEVEMIR in an insulin pump.. Inject LEVEMIR under your skin (subcutaneously) in your upper arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into vein or muscle.. Change injection sites within the area you choose with each dose. Do not inject into the exact same spot for each injection.. Read the instructions for use that comes with your LEVEMIR. Talk to your healthcare provider if you have any questions. Your healthcare provider should show you how to inject LEVEMIR before you start taking it.. Your healthcare provider will decide which type of LEVEMIR to prescribe for you.LEVEMIR comes in: 10 mL vials (small bottles) for use with syringe3 mL LEVEMIR FlexPen(R) 10 mL vials (small bottles) for use with syringe. mL LEVEMIR FlexPen(R) If you take too much LEVEMIR, 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 (lose consciousness).. If you forget to take your dose of LEVEMIR, 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. increased thirstfrequent urinationdrowsinessloss of appetite hard time breathing fruity smell on the breathhigh amounts of sugar and ketones in your urinenausea, vomiting (throwing up) or stomach pain. increased thirst. frequent urination. drowsiness. loss of appetite a hard time breathing fruity smell on the breath. high amounts of sugar and ketones in your urine. nausea, vomiting (throwing up) or stomach pain. Do not share needles, insulin pens or syringes with others.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. illnessstressother medicines you takechange in dietchange in physical activity or exercise. illness. stress. other medicines you take. change in diet. change in physical activity or exercise. Alcohol. Drinking alcohol may affect your blood sugar when you take LEVEMIR.. Driving and operating machinery. You may have trouble paying attention 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 for you to drive if you often have:low blood sugar (hypoglycemia)decreased or no warning signs of low blood sugar. low blood sugar (hypoglycemia). decreased or no warning signs of low blood sugar. Low blood sugar (hypoglycemia). Symptoms of low blood sugar may include:. dizziness or lightheadedness. shakiness. hunger. fast heart beat. tingling in your hands, feet, lips or tongue trouble concentrating or confusion. blurred vision. slurred speech. anxiety or mood changes. headache. sweating. Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) the area where you inject your insulin to help prevent these skin changes from happening. Do not inject insulin into areas of skin that have thickening or pits. Serious allergic reactions. LEVEMIR can cause life threatening symptoms. Get medical help right away if you have any of these symptoms of an allergic reaction:. rash all over your body. itching. shortness of breath. trouble breathing (wheezing). fast heartbeat. sweating. feel faint. Low blood sugar (hypoglycemia). See What are the possible side effects of LEVEMIR for more information on low blood sugar (hypoglycemia).. Reactions 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. Weight gain. This can occur with any insulin therapy. Talk to your healthcare provider about how LEVEMIR can affect your weight.. Keep all unopened LEVEMIR in the refrigerator between 36F to 46F (2C to 8C). Unopened LEVEMIR can be kept until the expiration date on the label if the medicine has been stored in refrigerator.. If refrigeration is not possible, you can keep the unopened LEVEMIR at room temperature below 86F (30C). Throw away LEVEMIR 42 days after it is first kept out of the refrigerator.. Do not freeze. Do not use LEVEMIR if it has been frozen.. Keep unopened LEVEMIR in the carton to protect it from light.. Vials Keep opened vials of LEVEMIR in the refrigerator or at room temperature below 86F (30C) away from direct heat or light. Throw away vial that has always been kept in the refrigerator after 42 days of use, even if there is insulin left in the vial. Throw away vial that has been kept at room temperature 42 days after it is first kept out of the refrigerator, even if there is insulin left in the vial.. Keep opened vials of LEVEMIR in the refrigerator or at room temperature below 86F (30C) away from direct heat or light. Throw away vial that has always been kept in the refrigerator after 42 days of use, even if there is insulin left in the vial. Throw away vial that has been kept at room temperature 42 days after it is first kept out of the refrigerator, even if there is insulin left in the vial.. LEVEMIR FlexPenKeep at room temperature below 86F (30C) for up to 42 days. Do not store LEVEMIR FlexPen that you are using in the refrigerator. Do not store LEVEMIR with the needle attached.Keep LEVEMIR FlexPen away from direct heat or light.Throw away used LEVEMIR FlexPens after 42 days, even if there is insulin left in them.. Keep at room temperature below 86F (30C) for up to 42 days. Do not store LEVEMIR FlexPen that you are using in the refrigerator. Do not store LEVEMIR with the needle attached.. Keep LEVEMIR FlexPen away from direct heat or light.. Throw away used LEVEMIR FlexPens after 42 days, even if there is insulin left in them.. 1. Check to make sure that you have the correct type of insulin. This is especially important if you use different types of insulin.. 2. Look at the vial and the insulin. The LEVEMIR insulin should be clear and colorless. The tamper-resistant cap should be in place before the first use. If the cap has been removed before your first use of the vial, or if the insulin is cloudy or colored, Do not use the insulin and return it to your pharmacy.. 3. Wash your hands with soap and water.. 4. If you are using new vial, pull off the tamper-resistant cap. 5. Do not roll or shake the vial. Shaking the vial right before the dose is drawn into the syringe may cause bubbles or foam. This can cause you to draw up the wrong dose of insulin. The insulin should be used only if it is clear and colorless.. 6. Pull back the plunger on your syringe until the black tip reaches the marking for the number of units you will inject.. 7. Push the needle through the rubber stopper into the vial.. 8. Push the plunger all the way in. This inserts air into the vial.. 9. Turn the vial and syringe upside down and slowly pull the plunger back to few units beyond the correct dose that you need.. 10. If there are air bubbles, tap the syringe gently with your finger to raise the air bubbles to the top of the needle. Then slowly push the plunger to the correct unit marking for your dose.. 11. Check to make sure you have the right dose of LEVEMIR in the syringe.. 12. Pull the syringe out of the vial. 13. Inject your LEVEMIR right away as instructed by your healthcare provider.. 1. Pinch your skin between two fingers, push the needle into the skinfold, using dart-like motion and push the plunger to inject the insulin under your skin. The needle will be straight in.. 2. Keep the needle under your skin for at least seconds to make sure you have injected all the insulin. After you pull the needle from your skin you may see drop of Levemir at the needle tip. This is normal and has no effect on the dose you just received.. 4. After each injection, remove the needlewithout recapping and dispose of it in puncture-resistant container. Used syringes, needles, and lancets should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.. LEVEMIR FlexPen should not be used by people who are blind or have severe eyesight problems without the help of person who has good eyesight and who is trained to use the LEVEMIR FlexPen the right way.. LEVEMIR FlexPen. NovoFine disposable needles. Alcohol swab. Always use new needle for each injection to cut down the chance of infection and to prevent blocked needles.. Be careful not to bend or damage the needle before use.. To reduce the risk of needle sticks, never put the inner needle cap back on the needle. Do not recap the needle with the small inner cap. Recapping with this small part can increase your chances of having needle stick injury. Put the needle 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.. Attach new NovoFine needle.. Remove the big outer needle cap and the inner needle cap.. Do an airshot as described in Giving the airshot before each injection (see diagram through G).. Put the big outer needle cap onto the needle. Do not put on the inner needle cap.. Turn the dose selector so the dose indicator window shows 20 units.. Hold the LEVEMIR FlexPen so the needle is pointing down.. Press the push-button all the way in.. Remove the needle from the LEVEMIR FlexPen after each injection. This helps to cut down your chance of infection, prevent leakage of insulin. Be careful when handling used needles to avoid needle sticks and transfer of infections.. Keep your LEVEMIR FlexPen and needles out of the reach of children. Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and LEVEMIR 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 safety measure, always carry spare insulin delivery device in case your LEVEMIR FlexPen is lost or damaged. Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave it in car or other location where it can get too hot or too cold.. Figure 4A. Figure 4B. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 1. Figure of Levemir FlexPen and Needle. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere:Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)] Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)] Adverse reactions associated with LEVEMIR include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus (6)To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience. Because 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.The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in Tables 1-4 below. See Tables and for the hypoglycemia findings.Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type diabetes (adverse reactions with incidence >= 5%)LEVEMIR, %(n 767)NPH, %(n 388)Upper respiratory tract infection26.121.4Headache22.622.7Pharyngitis9.58.0Influenza-like illness7.87.0Abdominal Pain6.02.6Table 2: Adverse reactions (excluding hypoglycemia) in 26-week trial comparing insulin aspart LEVEMIR to insulin aspart insulin glargine in adults with type diabetes (adverse reactions with incidence >= 5%)LEVEMIR, %(n 161)Glargine, %(n 159)Upper respiratory tract infection26.732.1Headache14.319.5Back pain8.16.3Influenza-like illness6.28.2Gastroenteritis5.64.4Bronchitis5.01.9Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type diabetes (adverse reactions with incidence >= 5%)LEVEMIR, %(n 432)NPH, %(n 437)Upper respiratory tract infection12.511.2Headache6.55.3Table 4: Adverse reactions (excluding hypoglycemia) in 26-week clinical trial of children and adolescents with type diabetes (adverse reactions with incidence >= 5%)LEVEMIR, %(n 232)NPH, %(n 115)Upper respiratory tract infection35.842.6Headache31.032.2Pharyngitis17.220.9Gastroenteritis16.811.3Influenza-like illness13.820.9Abdominal pain13.413.0Pyrexia10.36.1Cough8.24.3Viral infection7.37.8Nausea6.57.0Rhinitis6.53.5Vomiting6.510.4HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR [see Warnings and Precautions (5.3)]. Tables and summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either blood glucose below 50 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose 56 mg/dL (<50 mg/dL in Study and C) that was self-treated by the patient.The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for description of the study designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see Tables and 6). Table 5: Hypoglycemia in Patients with Type DiabetesStudy AType DiabetesAdults16 weeksIn combination withinsulin aspartStudy BType DiabetesAdults26 weeks In combination withinsulin aspartStudy CType DiabetesAdults24 weeksIn combination withregular insulinStudy DType DiabetesPediatrics26 weeksIn combination withinsulin aspartTwice-DailyLEVEMIRTwice-DailyNPHTwice-DailyLEVEMIROnce-Daily GlargineOnce-Daily LEVEMIROnce-Daily NPHOnce- or Twice Daily LEVEMIROnce- or Twice Daily NPHSevere hypoglycemiaPercent of patients with at least event (n/total N)8.7(24/276)10.6(14/132)5.0(8/161)10.1(16/159)7.5(37/491)10.2(26/256)15.9(37/232)20.0(23/115)Event/patient/year0.520.430.130.310.350.320.910.99Non-severe hypoglycemiaPercent of patients (n/total N)88.0(243/276)89.4(118/132)82.0(132/161)77.4(123/159)88.4(434/491)87.9(225/256)93.1(216/232)95.7(110/115)Event/patient/year26.437.520.221.831.133.431.637.0Table 6: Hypoglycemia in Patients with Type DiabetesStudy EType DiabetesAdults24 weeksIn combination withoral agentsStudy FType DiabetesAdults22 weeksIn combination withinsulin aspartTwice-Daily LEVEMIRTwice-Daily NPHOnce- or Twice Daily LEVEMIROnce- or Twice Daily NPHSevere hypoglycemiaPercent of patients with at least event (n/total N)0.4(1/237)2.5(6/238)1.5(3/195)4.0(8/199)Event/patient/year0.010.080.040.13Non-severe hypoglycemiaPercent of patients (n/total N)40.5(96/237)64.3(153/238)32.3(63/195)32.2(64/199)Event/patient/year3.56.91.62.0Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.LipodystrophyLong-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].Weight GainWeight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.Peripheral EdemaInsulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.Allergic ReactionsLocal AllergyAs with any insulin therapy, patients taking LEVEMIR may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy.Rotation of the injection site within given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in few days to few weeks.Systemic AllergySevere, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR, and may be life-threatening [see Warnings and Precautions (5.4)].Antibody ProductionAll insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase clinical trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic control.. Hypoglycemia. Insulin Initiation and Intensification of Glucose Control. Lipodystrophy. Weight Gain. Peripheral Edema. Allergic Reactions. Antibody Production. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of LEVEMIR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Medication errors have been reported during post-approval use of LEVEMIR in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed always to verify the insulin label before each injection.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.In fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times human dose of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.. 12.2 Pharmacodynamics. Insulin detemir is soluble, long-acting basal human insulin analog with up to 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to 24 hours (24 hours was the end of the observation period).Figure 2: Activity Profiles in Patients with Type Diabetes in 24-hour Glucose Clamp Study For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum effect from to hours up to approximately 14 hours after dose administration. Figure shows glucose infusion rate results from 16-hour glucose clamp study in patients with type diabetes. The clamp study was terminated at 16 hours according to protocol.Figure 3: Activity Profiles in Patients with Type Diabetes in 16-hour Glucose Clamp Study. 12.3 Pharmacokinetics. Absorption and BioavailabilityAfter subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%.Distribution and EliminationMore than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous administration in patients with type diabetes, insulin detemir has terminal half-life of to hours depending on dose. Specific PopulationsChildren and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children (6-12 years), adolescents (13-17 years), and adults with type diabetes. In children, the insulin detemir plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between adolescents and adults.Geriatrics- In clinical trial investigating differences in pharmacokinetics of single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (>=68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin preparations, LEVEMIR should always be titrated according to individual requirements.Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females.Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were investigated in clamp study comparing patients with type diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations.Renal impairment- single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal impairment [see Warnings and Precautions (5.5)].Hepatic impairment- single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic impairment with corresponding increase in apparent clearance. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see Warnings and Precautions (5.6)].Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied [see Use in Specific Populations (8.1)].Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.. Figure 2: Activity Profiles in Patients with Type Diabetes in 24-hour Glucose Clamp Study. Figure 3: Activity Profiles in Patients with Type Diabetes in 16-hour Glucose Clamp Study.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with type diabetes mellitus, 347 pediatric patients with type diabetes mellitus, and 869 adults with type diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily insulin glargine in an open-label, randomized, parallel study of 320 patients with type diabetes. The evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin (HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine. Type Diabetes AdultIn 16-week open-label clinical study (Study A, n=409), adults with type diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 7). Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose (FPG), or body weight. In 26-week, open-label clinical study (Study B, n=320), adults with type diabetes were randomized to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine (administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated patients had decrease in HbA1c similar to that of insulin glargine-treated patients. In 24-week, non-blinded clinical study (Study C, n=749), adults with type diabetes were randomized to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination with regular human insulin before each meal. LEVEMIR and NPH insulin had similar effect on HbA1c. Table 7: Type Diabetes Mellitus AdultStudy AStudy BStudy CTreatment duration16 weeks26 weeks24 weeksTreatment in combination withNovoLog(R) (insulin aspart)NovoLog(R) (insulin aspart)Human Soluble Insulin(regular insulin)Twice-dailyLEVEMIRTwice-dailyNPHTwice-daily LEVEMIROnce-daily insulin glargineOnce-daily LEVEMIROnce-daily NPHNumber of patients treated276133161159492257HbA1c (%) Baseline HbA1c8.68.58.98.88.48.3 Adj. mean change from baseline-0.8-0.7-0.6-0.5-0.10.0 LEVEMIR NPH 95% CI for Treatment difference-0.2(-0.3, -0.0)-0.0(-0.2, 0.2)-0.1(-0.3, 0.0)Basal insulin dose (units/day) Baseline mean212427231224 Mean change from baseline161010492Total insulin dose (units/day) Baseline mean485456514657 Mean change from baseline171096113Fasting blood glucose (mg/dL) Baseline mean209220153150213206 Adj. mean change from baseline-44-9-38-41-30-9Body weight (kg) Baseline mean74.675.577.575.176.576.9 Mean change from baseline0.20.80.51.0-0.30.3Baseline values were included as covariates in an ANCOVA analysis. Type Diabetes PediatricIn an open-label clinical study (Study D, n=347), pediatric patients (age range to 17) with type diabetes were randomized to 26 weeks of treatment with LEVEMIR or NPH insulin both of which were administered either once- or twice-daily (bedtime or morning and bedtime), at dosing frequency consistent with the number of daily basal insulin injections patient was taking prior to trial entry. Insulin aspart was administered before each meal. LEVEMIR-treated patients had decrease in HbA1c similar to that of NPH insulin (Table 8).Table 8: Type Diabetes Mellitus PediatricStudy DTreatment duration26 weeksTreatment in combination withNovoLog(R) (insulin aspart)Once- or Twice Daily LEVEMIR Once- or Twice Daily NPHNumber of subjects treated232115HbA1c (%) Baseline HbA1c8.88.8 Adj. mean change from baseline-0.7-0.8 LEVEMIR NPH 95% CI for Treatment difference0.1(-0.1, 0.3)Basal insulin dose (units/day) Baseline mean2426 Mean change from baseline86Total insulin dose (units/day) Baseline mean4850 Mean change from baseline97Fasting blood glucose (mg/dL) Baseline mean181181 Adj. mean change from baseline-39-21Body weight (kg) Baseline mean46.346.2 Mean change from baseline1.62.7Type Diabetes AdultIn 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast and evening) as part of regimen of stable combination therapy with one or two of the following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha-glucosidase inhibitor. All patients were insulin-naive at the time of randomization. LEVEMIR and NPH insulin similarly lowered HbA1c from baseline (Table 9).In 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type diabetes, LEVEMIR and NPH insulin were given once- or twice-daily as part of basal-bolus regimen with insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.Table 9: Type Diabetes Mellitus AdultStudy EStudy FTreatment duration24 weeks22 weeksTreatment in combination withoral agentsinsulin aspartTwice-dailyLEVEMIRTwice-dailyNPHOnce- or Twice Daily LEVEMIR Once- or Twice Daily NPHNumber of subjects treated237239195200HbA1c (%) Baseline HbA1c8.68.58.28.1 Adj. mean change from baseline-2.0-2.1-0.6-0.6 LEVEMIR NPH 95% CI for Treatment difference0.1(-0.0, 0.3)-0.1(-0.2, 0.1)Basal insulin dose (units/day) Baseline mean18172222 Mean change from baseline48282615Total insulin dose (units/day) Baseline mean--2222 Mean change from baseline--5742Fasting blood glucose (mg/dL) Baseline mean179173-- Adj. mean change from baseline-69-74--Body weight (kg) Baseline mean82.782.582.079.6 Mean change from baseline1.22.70.51.2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ]. Do not use in patients with hypersensitivity to LEVEMIR or any of its excipients (4). Do not use in patients with hypersensitivity to LEVEMIR or any of its excipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. LEVEMIR (insulin detemir [rDNA origin] injection) is sterile solution of insulin detemir for use as subcutaneous injection. Insulin detemir is long-acting (up to 24-hour duration of action) recombinant human insulin analog. LEVEMIR is produced by process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has molecular formula of C267H402O76N64S6 and molecular weight of 5916.9. It has the following structure:Figure 1: Structural Formula of insulin detemirLEVEMIR is clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains 100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has pH of approximately 7.4.. Figure of chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The starting dose should be individualized based on the type of diabetes and whether the patient is insulin-naive (2.1, 2.2, 2.3)Administer subcutaneously once daily or in divided doses twice daily. Once daily administration should be given with the evening meal or at bedtime (2.1)Rotate injection sites within an injection area (abdomen, thigh, or deltoid) to reduce the risk of lipodystrophy (2.1)Converting from other insulin therapies may require adjustment of timing and dose of LEVEMIR. Closely monitor glucoses especially upon converting to LEVEMIR and during the initial weeks thereafter (2.3). The starting dose should be individualized based on the type of diabetes and whether the patient is insulin-naive (2.1, 2.2, 2.3). Administer subcutaneously once daily or in divided doses twice daily. Once daily administration should be given with the evening meal or at bedtime (2.1). Rotate injection sites within an injection area (abdomen, thigh, or deltoid) to reduce the risk of lipodystrophy (2.1). Converting from other insulin therapies may require adjustment of timing and dose of LEVEMIR. Closely monitor glucoses especially upon converting to LEVEMIR and during the initial weeks thereafter (2.3). 2.1 Dosing. LEVEMIR is recombinant human insulin analog for once- or twice-daily subcutaneous administration. Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at bedtime.Patients who require twice-daily dosing can administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose.The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is essential in all patients receiving insulin therapy.Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].In patients with type diabetes, LEVEMIR must be used in regimen with rapid-acting or short-acting insulin.As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid) from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables, such as stress, intercurrent illness, or changes in co-administered medications or meal patterns.. 2.2 Initiation of LEVEMIR Therapy. The recommended starting dose of LEVEMIR in patients with type diabetes should be approximately one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be used to satisfy the remainder of the daily insulin requirements.The recommended starting dose of LEVEMIR in patients with type diabetes who are not currently treated with insulin is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or divided into twice daily regimen. LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages of LEVEMIR should be individualized under the supervision of healthcare provider.. 2.3 Converting to LEVEMIR from Other Insulin Therapies. If converting from insulin glargine to LEVEMIR, the change can be done on unit-to-unit basis.If converting from NPH insulin, the change can be done on unit-to-unit basis. However, some patients with type diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see Clinical Studies (14)].As with all insulins, close glucose monitoring is recommended during the transition and in the initial weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other concomitant antidiabetic treatment may need to be adjusted.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. LEVEMIR solution for injection 100 Unit per mL is available as:3 mL LEVEMIR FlexPen(R) 10 mL vial. mL LEVEMIR FlexPen(R) 10 mL vial. Solution for injection 100 Units/mL (U-100) in3 mL LEVEMIR FlexPen(R) 10 mL vial (3). mL LEVEMIR FlexPen(R) 10 mL vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. number of medications affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. The following are examples of medications that may increase the blood-glucose-lowering effect of insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics. The following are examples of medications that may reduce the blood-glucose-lowering effect of insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.. Certain drugs may affect glucose metabolism requiring insulin dose adjustment and close monitoring of blood glucose (7) The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine). (7). Certain drugs may affect glucose metabolism requiring insulin dose adjustment and close monitoring of blood glucose (7) The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine). (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients (3.9%) in the type diabetes trials and 309 of 1082 patients (28.6%) in the type diabetes trials were >=65 years of age. total of 52 (7 type and 45 type 2) patients (1.9%) were >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes, particularly for patients >=65 years of age in the type diabetes trials and for patients >=75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin detemir per mL (U-100).3 mL LEVEMIR FlexPen(R) NDC 54868-5883-0FlexPen is for use with NovoFine(R) disposable needles. Each FlexPen is for use by single patient. LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.. 16.2 Storage Unused (unopened) LEVEMIR should be stored in the refrigerator between and 8C (36 to 46F). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use LEVEMIR if it has been frozen.Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room temperature, below 30C (86F) as long as it is kept as cool as possible and away from direct heat and light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator, even if the FlexPen or vial still contains insulin.Vials:After initial use, vials should be stored in refrigerator, never in freezer. If refrigeration is not possible, the in-use vial can be kept unrefrigerated at room temperature, below 30C (86F) as long as it is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after they are first kept out of the refrigerator. LEVEMIR FlexPen:After initial use, the LEVEMIR FlexPen must NOT be stored in refrigerator and must NOT be stored with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at room temperature, below 30C (86F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days after they are first kept out of the refrigerator. The storage conditions are summarized in Table 10:Table 10: Storage Conditions for LEVEMIR FlexPen and vialNot in-use (unopened) RefrigeratedNot in-use (unopened) Room Temperature(below 30C)In-use (opened) mL LEVEMIR FlexPenUntil expiration date42 daysThe total time allowed at room temperature (below 30C) is 42 days regardless of whether the product is in-use or not in-use. 42 days Room Temperature (below 30C)(Do not refrigerate)10 mL vialUntil expiration date42 days 42 days Refrigerated or Room Temperature (below 30C). 16.3 Preparation and Handling. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to administration and should only be used if the solution appears clear and colorless. Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See Warnings and Precautions (5.2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use:LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.. LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.. LEVEMIR is long-acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. (1)Important Limitations of Use:Not recommended for treating diabetic ketoacidosis. Use intravenous, rapid-acting or short-acting insulin instead.. Not recommended for treating diabetic ketoacidosis. Use intravenous, rapid-acting or short-acting insulin instead.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). 17.1 Instructions for Patients. Patients should be informed that changes to insulin regimens must be made cautiously and only under medical supervision. Patients should be informed about the potential side effects of insulintherapy, including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the same body region), and allergic reactions. Patients should be informed that the 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 mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to always check the insulin label before each injection.LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution. Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or are contemplating pregnancy. Refer patients to the LEVEMIR Patient Information for additional information.. 17.2 Never Share LEVEMIR FlexPen Between Patients. Counsel patients that they should never share LEVEMIR FlexPen with another person, even if the needle is changed. Sharing of the FlexPen between patients may pose risk of transmission of infection.Novo Nordisk(R), Levemir(R), NovoLog(R), FlexPen(R), and NovoFine(R) are registered trademarks of Novo Nordisk A/S.LEVEMIR is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.FlexPen is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.(C) 2005-2012 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR contact:Novo Nordisk Inc.100 College Road WestPrinceton, NJ 085401-800-727-6500www.novonordisk-us.com. Additional barcode labeling by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.In fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times human dose of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, use caution when administering LEVEMIR to nursing woman. Use of LEVEMIR is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

OVERDOSAGE SECTION.

10 OVERDOSAGE. An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia. 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. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package Label Principal Display Panel 3 mL FlexPen. NDC 54868-5883-0List 643910Levemir(R) FlexPen(R) Insulin detemir (rDNA origin) injection100 units/mL (U-100)5x3 mL Prefilled PensFor subcutaneous use onlyRx OnlySingle Patient use onlyFor use with NovoFine(R) disposable needles.Keep in cold place.Store at - 8C (36 46F).Avoid freezing.Protect from light.. Levemir FlexPen Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been established in pediatric patients (age to 17 years) with type diabetes [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than years of age with type diabetes. LEVEMIR has not been studied in pediatric patients with type diabetes.The dose recommendation when converting to LEVEMIR is the same as that described for adults [see Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Insulin detemir is soluble, long-acting basal human insulin analog with up to 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to 24 hours (24 hours was the end of the observation period).Figure 2: Activity Profiles in Patients with Type Diabetes in 24-hour Glucose Clamp Study For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum effect from to hours up to approximately 14 hours after dose administration. Figure shows glucose infusion rate results from 16-hour glucose clamp study in patients with type diabetes. The clamp study was terminated at 16 hours according to protocol.Figure 3: Activity Profiles in Patients with Type Diabetes in 16-hour Glucose Clamp Study.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and BioavailabilityAfter subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%.Distribution and EliminationMore than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous administration in patients with type diabetes, insulin detemir has terminal half-life of to hours depending on dose. Specific PopulationsChildren and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children (6-12 years), adolescents (13-17 years), and adults with type diabetes. In children, the insulin detemir plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between adolescents and adults.Geriatrics- In clinical trial investigating differences in pharmacokinetics of single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (>=68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin preparations, LEVEMIR should always be titrated according to individual requirements.Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females.Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were investigated in clamp study comparing patients with type diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations.Renal impairment- single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal impairment [see Warnings and Precautions (5.5)].Hepatic impairment- single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic impairment with corresponding increase in apparent clearance. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see Warnings and Precautions (5.6)].Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied [see Use in Specific Populations (8.1)].Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category C: In fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times human dose of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug-dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at dose of 900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity.There are no well-controlled clinical studies of the use of LEVEMIR in pregnant women. Patients should be advised to discuss with their healthcare provider if they intend to, or if they become, pregnant. Because animal reproduction studies are not always predictive of human response, LEVEMIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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.

SPL UNCLASSIFIED SECTION.

2.1 Dosing. LEVEMIR is recombinant human insulin analog for once- or twice-daily subcutaneous administration. Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at bedtime.Patients who require twice-daily dosing can administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose.The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is essential in all patients receiving insulin therapy.Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].In patients with type diabetes, LEVEMIR must be used in regimen with rapid-acting or short-acting insulin.As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid) from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables, such as stress, intercurrent illness, or changes in co-administered medications or meal patterns.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy category C: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1)Pediatric: Has not been studied in children with type diabetes. Has not been studied in children with type diabetes 6 years of age (8.4). 8.1 Pregnancy. Pregnancy Category C: In fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times human dose of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug-dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at dose of 900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity.There are no well-controlled clinical studies of the use of LEVEMIR in pregnant women. Patients should be advised to discuss with their healthcare provider if they intend to, or if they become, pregnant. Because animal reproduction studies are not always predictive of human response, LEVEMIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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.. 8.3 Nursing Mothers. It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, use caution when administering LEVEMIR to nursing woman. Use of LEVEMIR is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.. 8.4 Pediatric Use. The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been established in pediatric patients (age to 17 years) with type diabetes [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than years of age with type diabetes. LEVEMIR has not been studied in pediatric patients with type diabetes.The dose recommendation when converting to LEVEMIR is the same as that described for adults [see Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose.. 8.5 Geriatric Use. In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients (3.9%) in the type diabetes trials and 309 of 1082 patients (28.6%) in the type diabetes trials were >=65 years of age. total of 52 (7 type and 45 type 2) patients (1.9%) were >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes, particularly for patients >=65 years of age in the type diabetes trials and for patients >=75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Dose adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision (5.1)Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously because severe hypoglycemia can occur (5.2)Hypoglycemia is the most common adverse reaction of insulin therapy and may be life-threatening (5.3, 6.1)Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. (5.4)Renal or hepatic impairment: May require adjustment of the LEVEMIR dose (5.5, 5.6).. Dose adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision (5.1). Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously because severe hypoglycemia can occur (5.2). Hypoglycemia is the most common adverse reaction of insulin therapy and may be life-threatening (5.3, 6.1). Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. (5.4). Renal or hepatic impairment: May require adjustment of the LEVEMIR dose (5.5, 5.6).. 5.1 Dosage Adjustment and Monitoring. Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.Changes in insulin strength, manufacturer, type, or method of administration may result in the need for change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.As with all insulin preparations, the time course of action for LEVEMIR may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.. 5.2 Administration. LEVEMIR should only be administered subcutaneously.Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.3)].Do not use LEVEMIR in insulin infusion pumps.Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR and the mixed insulin may be altered in an unpredictable manner.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR.The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast 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.Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patients awareness of hypoglycemia.. 5.4 Hypersensitivity and Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR.. 5.5 Renal Impairment. No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal impairment [see Clinical Pharmacology (12.3)].. 5.6 Hepatic Impairment. Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)].. 5.7 Drug Interactions. Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia [see Drug Interactions (7)].