RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2) 1/2019. Warnings and Precautions, Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2) 1/2019.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEAranesp(R) (Air-uh-nesp)(darbepoetin alfa)Read this Medication Guide: before you start Aranesp. if you are told by your healthcare provider that there is new information about Aranesp. if you are told by your healthcare provider that you may inject Aranesp at home, read this Medication Guide each time you receive new supply of medicine. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Talk with your healthcare provider regularly about the use of Aranesp and ask if there is new information about Aranesp.What is the most important information should know about AranespAranesp may cause serious side effects that can lead to death, including: For people with cancer: Your tumor may grow faster and you may die sooner if you choose to take Aranesp. Your healthcare provider will talk with you about these risks. For all people who take Aranesp, including people with cancer or chronic kidney disease Serious heart problems, such as heart attack or heart failure, and stroke. You may die sooner if you are treated with Aranesp to increase red blood cells (RBCs) to near the same level found in healthy people. Blood clots. Blood clots may happen at any time while taking Aranesp. If you are receiving Aranesp for any reason and you are going to have surgery, talk to your healthcare provider about whether or not you need to take blood thinner to lessen the chance of blood clots during or following surgery. Blood clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus). Call your healthcare provider or get medical help right away if you have any of these symptoms: Chest pain Trouble breathing or shortness of breath Pain in your legs, with or without swelling cool or pale arm or leg Sudden confusion, trouble speaking, or trouble understanding others speech Sudden numbness or weakness in your face, arm, or leg, especially on one side of your body Sudden trouble seeing Sudden trouble walking, dizziness, loss of balance or coordination Loss of consciousness (fainting) Hemodialysis vascular access stops workingSee What are the possible side effects of Aranesp below for more information.If you decide to take Aranesp, your healthcare provider should prescribe the smallest dose of Aranesp that is necessary to reduce your chance of needing red blood cell transfusions.What is AranespAranesp is prescription medicine used to treat anemia. People with anemia have lower-than-normal number of RBCs. Aranesp works like the human protein called erythropoietin to help your body make more RBCs. Aranesp is used to reduce or avoid the need for RBC transfusions.Aranesp may be used to treat anemia if it is caused by: Chronic kidney disease (you may or may not be on dialysis). Chemotherapy that will be used for at least two months after starting Aranesp.If your hemoglobin level stays too high or if your hemoglobin goes up too quickly, this may lead to serious health problems which may result in death. These serious health problems may happen if you take Aranesp, even if you do not have an increase in your hemoglobin level.Aranesp has not been proven to improve the quality of life, fatigue, or well-being.Aranesp should not be used for the treatment of anemia: If you have cancer and you will not be receiving chemotherapy that may cause anemia. If you have cancer that has high chance of being cured. Talk with your healthcare provider about the kind of cancer you have. If your anemia caused by chemotherapy treatment can be managed by RBC transfusion. In place of emergency treatment for anemia (RBC transfusions).It is not known if Aranesp is safe and effective in children who have cancer.Who should not take AranespDo not take Aranesp if you:Have cancer and have not been counseled by your healthcare provider about treatment with Aranesp. Have high blood pressure that is not controlled (uncontrolled hypertension). Have been told by your healthcare provider that you have or have ever had type of anemia called Pure Red Cell Aplasia (PRCA) that starts after treatment with Aranesp or other erythropoietin protein medicines. Have had serious allergic reaction to Aranesp.Before taking Aranesp, tell your healthcare provider about all of your medical conditions, including if you:Have heart disease. Have high blood pressure. Have had seizure (convulsion) or stroke. Are allergic to latex. The needle cover on the prefilled syringe contains latex. Receive dialysis treatment. Are pregnant or plan to become pregnant. It is not known if Aranesp may harm your unborn baby. Talk to your healthcare provider about possible pregnancy and birth control choices that are right for you. Are breastfeeding or plan to breastfeed. It is not known if Aranesp passes into breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take AranespIf you or your caregiver has been trained to give Aranesp shots (injections) at home: Be sure that you read, understand, and follow the Instructions for Use that come with Aranesp. Take Aranesp exactly as your healthcare provider tells you to. Do not change the dose of Aranesp unless told to do so by your healthcare provider. Your healthcare provider will show you how much Aranesp to use, how to inject it, how often it should be injected, and how to safely throw away the used vials, syringes, and needles. If you miss dose of Aranesp, call your healthcare provider right away and ask what to do. If you take more than the prescribed dose of Aranesp, call your healthcare provider right away. During treatment with Aranesp, continue to follow your healthcare providers instructions for diet and medicines. Have your blood pressure checked as instructed by your healthcare provider.What are the possible side effects of AranespAranesp may cause serious side effects, including:See What is the most important information should know about Aranesp High blood pressure. High blood pressure is common side effect of Aranesp in people with chronic kidney disease. Your blood pressure may go up or be difficult to control with blood pressure medicine while taking Aranesp. This can happen even if you have never had high blood pressure before. Your healthcare provider should check your blood pressure often. If your blood pressure does go up, your healthcare provider may prescribe new or more blood pressure medicine.Seizures. If you have any seizures while taking Aranesp, get medical help right away and tell your healthcare provider.Antibodies to Aranesp. Your body may make antibodies to Aranesp. These antibodies can block or lessen your bodys ability to make RBCs and cause you to have severe anemia. Call your healthcare provider if you have unusual tiredness, lack of energy, dizziness, or fainting. You may need to stop taking Aranesp. Serious allergic reactions. Serious allergic reactions can cause skin rash, itching, shortness of breath, wheezing, dizziness and fainting because of drop in blood pressure, swelling around your mouth or eyes, fast pulse, or sweating. If you have serious allergic reaction, stop using Aranesp and call your healthcare provider or get medical help right away. Severe skin reactions. Signs and symptoms of severe skin reactions with Aranesp may include: skin rash with itching, blisters, skin sores, peeling or areas of skin coming off. If you have any signs or symptoms of severe skin reaction, stop using Aranesp and call your healthcare provider or get medical help right away.Common side effects of ARANESP include:shortness of breath cough low blood pressure during dialysis abdominal pain edema (swelling) of the arms or legsThese are not all the possible side effects of ARANESP. Your healthcare provider can give you more complete list. Tell your healthcare provider about any side effects that bother you or that do not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store AranespDo not shake Aranesp. Store Aranesp in the carton it comes in to protect it from light. Store Aranesp in the refrigerator between 36F to 46F (2C to 8C). Do not freeze Aranesp. Do not use Aranesp that has been frozen. Throw away the Aranesp vial or prefilled syringe after one use. Do not re-use even if there is medicine left. Keep Aranesp and all medicines out of the reach of children.General information about Aranesp.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use Aranesp for condition for which it was not prescribed. Do not give Aranesp to other people even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Aranesp that is written for healthcare professionals.What are the ingredients in AranespActive ingredient: darbepoetin alfa Inactive ngredients: polysorbate 80, sodium chloride, sodium phosphate dibasic anhydrous, and sodium phosphate monobasic monohydrate in Water for Injection, USP. Manufactured by: Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 U.S.A.U.S. License Number 1080 (C) 2001-2018 Amgen Inc. All rights reserved. 1xxxxxx v8 PMV 5For more information, go to the following website: www.aranesp.com or call 1-800-77-AMGEN.This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2018. before you start Aranesp. if you are told by your healthcare provider that there is new information about Aranesp. if you are told by your healthcare provider that you may inject Aranesp at home, read this Medication Guide each time you receive new supply of medicine. Your tumor may grow faster and you may die sooner if you choose to take Aranesp. Your healthcare provider will talk with you about these risks.. Serious heart problems, such as heart attack or heart failure, and stroke. You may die sooner if you are treated with Aranesp to increase red blood cells (RBCs) to near the same level found in healthy people. Blood clots. Blood clots may happen at any time while taking Aranesp. If you are receiving Aranesp for any reason and you are going to have surgery, talk to your healthcare provider about whether or not you need to take blood thinner to lessen the chance of blood clots during or following surgery. Blood clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus). Call your healthcare provider or get medical help right away if you have any of these symptoms: Chest pain Trouble breathing or shortness of breath Pain in your legs, with or without swelling cool or pale arm or leg Sudden confusion, trouble speaking, or trouble understanding others speech Sudden numbness or weakness in your face, arm, or leg, especially on one side of your body Sudden trouble seeing Sudden trouble walking, dizziness, loss of balance or coordination Loss of consciousness (fainting) Hemodialysis vascular access stops working. Chronic kidney disease (you may or may not be on dialysis). Chemotherapy that will be used for at least two months after starting Aranesp.. If you have cancer and you will not be receiving chemotherapy that may cause anemia. If you have cancer that has high chance of being cured. Talk with your healthcare provider about the kind of cancer you have. If your anemia caused by chemotherapy treatment can be managed by RBC transfusion. In place of emergency treatment for anemia (RBC transfusions).. Have cancer and have not been counseled by your healthcare provider about treatment with Aranesp. Have high blood pressure that is not controlled (uncontrolled hypertension). Have been told by your healthcare provider that you have or have ever had type of anemia called Pure Red Cell Aplasia (PRCA) that starts after treatment with Aranesp or other erythropoietin protein medicines. Have had serious allergic reaction to Aranesp.. Have heart disease. Have high blood pressure. Have had seizure (convulsion) or stroke. Are allergic to latex. The needle cover on the prefilled syringe contains latex. Receive dialysis treatment. Are pregnant or plan to become pregnant. It is not known if Aranesp may harm your unborn baby. Talk to your healthcare provider about possible pregnancy and birth control choices that are right for you. Are breastfeeding or plan to breastfeed. It is not known if Aranesp passes into breast milk.. If you or your caregiver has been trained to give Aranesp shots (injections) at home: Be sure that you read, understand, and follow the Instructions for Use that come with Aranesp. Take Aranesp exactly as your healthcare provider tells you to. Do not change the dose of Aranesp unless told to do so by your healthcare provider. Your healthcare provider will show you how much Aranesp to use, how to inject it, how often it should be injected, and how to safely throw away the used vials, syringes, and needles. If you miss dose of Aranesp, call your healthcare provider right away and ask what to do. If you take more than the prescribed dose of Aranesp, call your healthcare provider right away. During treatment with Aranesp, continue to follow your healthcare providers instructions for diet and medicines. Have your blood pressure checked as instructed by your healthcare provider.. See What is the most important information should know about Aranesp High blood pressure. High blood pressure is common side effect of Aranesp in people with chronic kidney disease. Your blood pressure may go up or be difficult to control with blood pressure medicine while taking Aranesp. This can happen even if you have never had high blood pressure before. Your healthcare provider should check your blood pressure often. If your blood pressure does go up, your healthcare provider may prescribe new or more blood pressure medicine.. Seizures. If you have any seizures while taking Aranesp, get medical help right away and tell your healthcare provider.. Antibodies to Aranesp. Your body may make antibodies to Aranesp. These antibodies can block or lessen your bodys ability to make RBCs and cause you to have severe anemia. Call your healthcare provider if you have unusual tiredness, lack of energy, dizziness, or fainting. You may need to stop taking Aranesp. Serious allergic reactions. Serious allergic reactions can cause skin rash, itching, shortness of breath, wheezing, dizziness and fainting because of drop in blood pressure, swelling around your mouth or eyes, fast pulse, or sweating. If you have serious allergic reaction, stop using Aranesp and call your healthcare provider or get medical help right away. Severe skin reactions. Signs and symptoms of severe skin reactions with Aranesp may include: skin rash with itching, blisters, skin sores, peeling or areas of skin coming off. If you have any signs or symptoms of severe skin reaction, stop using Aranesp and call your healthcare provider or get medical help right away.. shortness of breath cough low blood pressure during dialysis abdominal pain edema (swelling) of the arms or legs. Do not shake Aranesp. Store Aranesp in the carton it comes in to protect it from light. Store Aranesp in the refrigerator between 36F to 46F (2C to 8C). Do not freeze Aranesp. Do not use Aranesp that has been frozen. Throw away the Aranesp vial or prefilled syringe after one use. Do not re-use even if there is medicine left.

SPL UNCLASSIFIED SECTION.

1.1 Anemia Due to Chronic Kidney Disease. Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Risk SummaryThe limited available data on Aranesp use in pregnant women are insufficient to determine drug-associated risk of major birth defects or miscarriage. In animal reproductive and developmental toxicity studies, Aranesp increased early post-implantation loss at doses approximating the clinical recommended starting doses see Data ]. Consider the benefits and risks of Aranesp for the mother and possible risks to the fetus when prescribing Aranesp to pregnant woman.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.DataAnimal DataWhen Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days to 15) and rabbits (gestational days to 18), there was no evidence of embryofetal toxicity or other adverse outcomes at the intravenous doses tested, up to 20 mcg/kg/day. This animal dose level of 20 mcg/kg/day is approximately 20-fold higher than the clinical recommended starting dose, depending on the patients treatment indication. Slightly reduced fetal weights were observed when rat and rabbit mothers received doses of mcg/kg or more, causing exaggerated pharmacological effects in both the rat and rabbit dams. This dose of mcg/kg is near the clinical recommended starting dose. While no adverse effects on uterine implantation occurred in animals, in rat fertility study, there was an increase in early post-implantation loss at doses equal to or greater than 0.5 mcg/kg, administered times weekly. It is not clear whether the increased post-implantation loss reflects drug effect on the uterine environment or on the conceptus. No significant placental transfer of Aranesp was observed in rats; placental transfer was not evaluated in rabbits.In peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation (day 6) throughout pregnancy and lactation (day 23). The lowest dose tested, 0.5 mcg/kg, did not cause fetal toxicity; this dose is approximately equivalent to the clinical recommended starting dose. At maternal doses of 2.5 mcg/kg and higher, pups had decreased fetal body weights, which correlated with slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Aranesp related effects were apparent for their offspring (F2 generation fetuses).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of Aranesp in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Aranesp and any potential adverse effects on the breastfed child from Aranesp or from the underlying maternal condition.. 8.4 Pediatric Use. Pediatric Patients with CKDThe safety and effectiveness of Aranesp in pediatric patients with CKD receiving and not receiving dialysis have been established in the age groups month to 16 years old. No data are available in pediatric patients less than month old. Use of Aranesp in these age groups is supported by evidence from adequate and well-controlled studies of Aranesp in adults with additional data from randomized trial evaluating two schedules (weekly and every week dosing) in 114 pediatric patients to 16 years of age receiving darbepoetin alfa, and an observational registry study in 319 pediatric patients <1 to 16 years of age receiving darbepoetin alfa. Aranesp safety and efficacy were similar between adults and pediatric patients with CKD receiving and not receiving dialysis when Aranesp was used for initial treatment of anemia or patients were transitioned from treatment with epoetin alfa to Aranesp [see Adverse Reactions 6.1 ), Clinical Pharmacology 12.3 and Clinical Studies 14.1 )].Pediatric Patients with CancerThe safety and efficacy of Aranesp in pediatric patients with cancer have not been established.. 8.5 Geriatric Use. Of the 1801 patients with CKD in clinical studies of Aranesp, 44% were age 65 and over, while 17% were age 75 and over. Of the 873 patients in clinical studies receiving Aranesp and concomitant cancer chemotherapy, 45% were age 65 and over, while 14% were age 75 and over. No differences in safety or efficacy were observed between older and younger patients.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseAranesp(R) (Air-uh-nesp)(darbepoetin alfa)Single-Dose VialUse these Instructions for Use if you or your caregiver has been trained to give Aranesp injections at home. Do not give yourself the injection unless you have received training from your healthcare provider. If you are not sure about giving the injection or if you have questions, ask your healthcare provider for help.Before reading these Instructions for Use, read the Medication Guide that comes with Aranesp for the most important information you need to know. When you receive your Aranesp vial and syringes make sure that:The name Aranesp appears on the carton and vial label. The expiration date on the vial label has not passed. Do not use vial of Aranesp after the expiration date on the label. The dose strength of the Aranesp vial (number of micrograms [mcg] in the colored square on the package and on the vial label) is the same as your healthcare provider prescribed. The Aranesp liquid in the vial is clear and colorless. Do not use Aranesp if the liquid in the vial looks discolored or cloudy, or if the liquid has lumps, flakes, or particles. The Aranesp vial has color cap on the top of the vial. Do not use vial of Aranesp if the color cap on the top of the vial has been removed or is missing. Use only the type of disposable syringe and needle that your healthcare provider has prescribed. Do not shake Aranesp. Shaking could cause Aranesp not to work. If you shake Aranesp, the solution in the vial may look foamy and should not be used. Do not freeze Aranesp. Do not use vial of Aranesp that has been frozen. Store Aranesp in the refrigerator between 36F to 46F (2C to 8C). Keep Aranesp away from light. Single-dose vials of Aranesp should be used only one time. Throw the vial away after use even if there is medicine left in the vial.How should prepare for an injection of AranespAlways keep an extra syringe and needle on hand. Follow your healthcare providers instructions on how to measure your dose of Aranesp. This dose will be measured in milliliter (mL) or cc (1 mL is the same as cc). Use syringe that is marked in tenths of mL (for example, 0.2 mL or 0.2 cc). Using the wrong syringe can lead to mistake in your dose and you could inject too much or too little Aranesp.Only use disposable syringes and needles. Use the syringes and needles only one time and then throw them away as instructed by your healthcare provider.Important: Follow these instructions exactly to help avoid infections.Preparing the dose:1. Remove the vial of Aranesp from the refrigerator. During this time, protect the solution from light. Keep the vial in its carton until you are ready to prepare the dose. Do not leave the vial in light. 2. Do not use single-dose vial of Aranesp more than one time. 3. Do not shake Aranesp. 4. Gather the other supplies you will need for your injection (vial, syringe, alcohol wipes, cotton ball, and puncture-proof container for throwing away the syringe and needle). See Figure 1. 5. Check the date on the Aranesp vial to be sure that the drug has not expired.6. Wash your hands well with soap and water before preparing the medicine. See Figure 2. 7. Flip off the protective color cap on the top of the vial. Do not remove the grey rubber stopper. Wipe the top of the grey rubber stopper with an alcohol wipe. See Figures and 4. 8. Check the package containing the syringe. If the package has been opened or damaged, do not use that syringe. Throw away the syringe in the puncture-proof disposable container. If the syringe package is undamaged, open the package and remove the syringe.9. Using syringe and needle that has been recommended by your healthcare provider, carefully remove the needle cover. See Figure 5. Then draw air into the syringe by pulling back on the plunger. The amount of air drawn into the syringe should be equal to the amount (mL or cc) of the Aranesp dose prescribed by your healthcare provider. See Figure 6. 10. With the vial on flat work surface, insert the needle straight down through the grey rubber stopper of the Aranesp vial. See Figure 7.11. Push the plunger of the syringe down to inject the air from the syringe into the vial of Aranesp. The air injected into the vial will allow Aranesp to be easily withdrawn into the syringe. See Figure 7.12. Keep the needle inside the vial. Turn the vial and syringe upside down. Be sure the tip of the needle is in the Aranesp liquid. Keep the vial upside down. Slowly pull back on the plunger to fill the syringe with Aranesp liquid to the number (mL or cc) that matches the dose your healthcare provider prescribed. See Figure 8.13. Keep the needle in the vial. Check for air bubbles in the syringe. small amount of air is harmless. Too large an air bubble will give you the wrong Aranesp dose. To remove air bubbles, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. Slowly push the plunger up to force the air bubbles out of the syringe. Keep the tip of the needle in the Aranesp liquid. Pull the plunger back to the number on the syringe that matches your dose. Check again for air bubbles. If there are still air bubbles, repeat the steps above to remove them. See Figures and 10. 14. Double-check that you have the correct dose in the syringe. Lay the vial down on its side with the needle still in it until after you have selected and prepared site for injection. Selecting and preparing the injection site:Aranesp can be injected into your body using two different ways (routes) as described below. Follow your healthcare providers instructions about how you should inject Aranesp. For patients on hemodialysis, the intravenous (IV) route is recommended.1. Subcutaneous Route: Aranesp can be injected directly into layer of fat under your skin. This is called subcutaneous injection. When giving subcutaneous injections, follow your healthcare providers instructions about changing the site for each injection. You may wish to write down the site where you have injected. Do not inject Aranesp into an area that is tender, red, bruised, hard, or has scars or stretch marks. Recommended sites for injection are shown in Figure 11 below, including: The outer area of the upper arms The abdomen (except for the 2-inch area around the navel) The front of the middle thighs The upper outer area of the buttocksClean the skin with an alcohol wipe where the injection is to be made. Be careful not to touch the skin that has been wiped clean. See Figure 12. Double-check that the correct amount of Aranesp is in the syringe. Remove the prepared syringe and needle from the vial of Aranesp and hold it in the hand that you will use to inject the medicine. Use the other hand to pinch fold of skin at the cleaned injection site. Do not touch the cleaned area of skin. See Figure 13. Hold the syringe like you would hold pencil. Use quick dart-like motion to insert the needle either straight up and down (90-degree angle) or at slight angle (45 degrees) into the skin. Inject the prescribed dose subcutaneously as directed by your doctor, nurse, or pharmacist. See Figure 14. Pull the needle out of the skin and press cotton ball or gauze over the injection site and hold it there for several seconds. Do not recap the needle. Dispose of the used syringe and needle as described below. Do not reuse syringes and needles.2. Intravenous Route: Aranesp can be injected in your vein through special access port placed by your healthcare provider. This type of Aranesp injection is called an intravenous (IV) injection. This route is usually for hemodialysis patients. If you have dialysis vascular access, make sure it is working by checking it as your healthcare provider has shown you. Be sure to let your healthcare provider know right away if you are having any problems, or if you have any questions. Wipe off the venous port of the hemodialysis tubing with an alcohol wipe. See Figure 15. Insert the needle of the syringe into the cleaned venous port and push the plunger all the way down to inject all the Aranesp. See Figure 16.Remove the syringe from the venous port. Do not recap the needle. Dispose of the used syringe and needle as described below. How should dispose of the vials, syringes, and needlesDo not reuse the single-dose vials, syringes, or needles. Throw away the vials, syringes, and needles as instructed by your healthcare provider or by following these steps:Do not throw the vials, syringes, or needles in the household trash or recycle. Do not put the needle cover back on the needle. Place all used needles and syringes in puncture-proof disposable container with lid. Do not use glass or clear plastic containers, or any container that will be recycled or returned to store. Keep the puncture-proof disposable container out of the reach of children. When the puncture-proof disposable container is full, tape around the cap or lid to make sure the cap or lid does not come off. Throw away the puncture-proof disposable container as instructed by your healthcare provider. There may be special state and local laws for disposing of used needles and syringes. Do not throw the puncture-proof disposable container in the household trash. Do not recycle. Keep Aranesp and all medicines out of reach of children. These Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 U.S.A.Revised: 05/2012(C) 2001-2012 Amgen Inc. All rights reserved.1xxxxxx v3 PMV 3. The name Aranesp appears on the carton and vial label. The expiration date on the vial label has not passed. Do not use vial of Aranesp after the expiration date on the label. The dose strength of the Aranesp vial (number of micrograms [mcg] in the colored square on the package and on the vial label) is the same as your healthcare provider prescribed. The Aranesp liquid in the vial is clear and colorless. Do not use Aranesp if the liquid in the vial looks discolored or cloudy, or if the liquid has lumps, flakes, or particles. The Aranesp vial has color cap on the top of the vial. Do not use vial of Aranesp if the color cap on the top of the vial has been removed or is missing. Use only the type of disposable syringe and needle that your healthcare provider has prescribed. Do not shake Aranesp. Shaking could cause Aranesp not to work. If you shake Aranesp, the solution in the vial may look foamy and should not be used. Do not freeze Aranesp. Do not use vial of Aranesp that has been frozen. Store Aranesp in the refrigerator between 36F to 46F (2C to 8C). Keep Aranesp away from light. Single-dose vials of Aranesp should be used only one time. Throw the vial away after use even if there is medicine left in the vial.. Always keep an extra syringe and needle on hand. Follow your healthcare providers instructions on how to measure your dose of Aranesp. This dose will be measured in milliliter (mL) or cc (1 mL is the same as cc). Use syringe that is marked in tenths of mL (for example, 0.2 mL or 0.2 cc). Using the wrong syringe can lead to mistake in your dose and you could inject too much or too little Aranesp.. Aranesp can be injected directly into layer of fat under your skin. This is called subcutaneous injection. When giving subcutaneous injections, follow your healthcare providers instructions about changing the site for each injection. You may wish to write down the site where you have injected. Do not inject Aranesp into an area that is tender, red, bruised, hard, or has scars or stretch marks. Recommended sites for injection are shown in Figure 11 below, including: The outer area of the upper arms The abdomen (except for the 2-inch area around the navel) The front of the middle thighs The upper outer area of the buttocks. Clean the skin with an alcohol wipe where the injection is to be made. Be careful not to touch the skin that has been wiped clean. See Figure 12. Double-check that the correct amount of Aranesp is in the syringe. Remove the prepared syringe and needle from the vial of Aranesp and hold it in the hand that you will use to inject the medicine. Use the other hand to pinch fold of skin at the cleaned injection site. Do not touch the cleaned area of skin. See Figure 13. Hold the syringe like you would hold pencil. Use quick dart-like motion to insert the needle either straight up and down (90-degree angle) or at slight angle (45 degrees) into the skin. Inject the prescribed dose subcutaneously as directed by your doctor, nurse, or pharmacist. See Figure 14. Pull the needle out of the skin and press cotton ball or gauze over the injection site and hold it there for several seconds. Do not recap the needle. Dispose of the used syringe and needle as described below. Do not reuse syringes and needles.. Aranesp can be injected in your vein through special access port placed by your healthcare provider. This type of Aranesp injection is called an intravenous (IV) injection. This route is usually for hemodialysis patients. If you have dialysis vascular access, make sure it is working by checking it as your healthcare provider has shown you. Be sure to let your healthcare provider know right away if you are having any problems, or if you have any questions. Wipe off the venous port of the hemodialysis tubing with an alcohol wipe. See Figure 15. Insert the needle of the syringe into the cleaned venous port and push the plunger all the way down to inject all the Aranesp. See Figure 16.. Remove the syringe from the venous port. Do not recap the needle. Dispose of the used syringe and needle as described below. Do not throw the vials, syringes, or needles in the household trash or recycle. Do not put the needle cover back on the needle. Place all used needles and syringes in puncture-proof disposable container with lid. Do not use glass or clear plastic containers, or any container that will be recycled or returned to store. Keep the puncture-proof disposable container out of the reach of children. When the puncture-proof disposable container is full, tape around the cap or lid to make sure the cap or lid does not come off. Throw away the puncture-proof disposable container as instructed by your healthcare provider. There may be special state and local laws for disposing of used needles and syringes. Do not throw the puncture-proof disposable container in the household trash. Do not recycle. Figure 1. Figure 2. Figure and 4. Figure and 6. Figure 7. Figure 8. Figure and 10. Figure 11. Figure 12. Figure 13. Figure 14. Figure 15. 16.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of Aranesp in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Aranesp and any potential adverse effects on the breastfed child from Aranesp or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of Aranesp has not been evaluated in long-term animal studies. In toxicity studies of approximately months duration in rats and dogs, no tumorigenic or unexpected mitogenic responses were observed in any tissue type.Aranesp was not mutagenic or clastogenic under the conditions tested. Aranesp was negative in the in vitro bacterial reverse mutation assay, the in vitro mammalian cell gene mutation assay (using CHO cells), and in the in vivo mouse erythrocyte micronucleus assay.Aranesp increased the incidence of post-implantation losses in rats. Male and female rats received intravenous doses prior to and during mating; then females were treated times weekly during the first trimester of gestation (gestation days 1, 3, 5, and 7). No effect on reproductive performance, fertility, or sperm assessment parameters were detected at any of the doses evaluated (up to 10 mcg/kg, administered times weekly). The dose of 10 mcg/kg is more than 10-fold higher than the clinical recommended starting dose. An increase in post-implantation fetal loss was seen at doses equal to or greater than 0.5 mcg/kg, administered times weekly. The dose of 0.5 mcg/kg is approximately equivalent to the clinical recommended starting dose. Signs of exaggerated pharmacology were not observed in the mother receiving 0.5 mcg/kg or less, but were observed at 2.5 mcg/kg and higher.

OVERDOSAGE SECTION.

10 OVERDOSAGE Aranesp overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Aranesp dosage and/or with phlebotomy, as clinically indicated [see Pharmacodynamics 12.2 ]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions 5.3 )].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL PREFILLED SYRINGE, 10 MCG. NDC 55513-098-04Single-Dose Prefilled Syringes with 27 Gauge Needles4 10 mcg/0.4 mL Prefilled SyringesAMGEN (R) Aranesp (R) SingleJect (R) (darbepoetin alfa)recombinantAlbumin Free10 mcg10 mcg/0.4 mLFor Intravenous or Subcutaneous Use OnlySterile Solution No PreservativeStore at to 8C (36 to 46F).Do Not Freeze or Shake. Protect from Light.This Product Contains Dry Natural Rubber.Rx OnlyU.S. License No. 1080(C)2014, 2016 Amgen Inc.Manufactured by Amgen Inc. Thousand Oaks, CA 91320-1799 U.S.A.. NDC 55513-098-04Single-Dose Prefilled Syringes with 27 Gauge Needles4 10 mcg/0.4 mL Prefilled SyringesAMGEN (R)Aranesp (R) SingleJect (R)(darbepoetin alfa)recombinantAlbumin Free10 mcg10 mcg/0.4 mLFor Intravenous or Subcutaneous Use OnlySterile Solution No PreservativeStore at to 8C (36 to 46F).Do Not Freeze or Shake. Protect from Light.This Product Contains Dry Natural Rubber.Rx OnlyU.S. License No. 1080(C)2014, 2016 Amgen Inc.Manufactured by Amgen Inc. Thousand Oaks, CA 91320-1799 U.S.A.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Pediatric Patients with CKDThe safety and effectiveness of Aranesp in pediatric patients with CKD receiving and not receiving dialysis have been established in the age groups month to 16 years old. No data are available in pediatric patients less than month old. Use of Aranesp in these age groups is supported by evidence from adequate and well-controlled studies of Aranesp in adults with additional data from randomized trial evaluating two schedules (weekly and every week dosing) in 114 pediatric patients to 16 years of age receiving darbepoetin alfa, and an observational registry study in 319 pediatric patients <1 to 16 years of age receiving darbepoetin alfa. Aranesp safety and efficacy were similar between adults and pediatric patients with CKD receiving and not receiving dialysis when Aranesp was used for initial treatment of anemia or patients were transitioned from treatment with epoetin alfa to Aranesp [see Adverse Reactions 6.1 ), Clinical Pharmacology 12.3 and Clinical Studies 14.1 )].Pediatric Patients with CancerThe safety and efficacy of Aranesp in pediatric patients with cancer have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Increased hemoglobin levels are not generally observed until to weeks after initiating treatment with Aranesp.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Adult Patients with CKDThe pharmacokinetics of Aranesp were studied in patients with CKD receiving or not receiving dialysis and patients with cancer receiving chemotherapy.Following intravenous administration of Aranesp to patients with CKD receiving dialysis, Aranesp serum concentration-time profiles were biphasic, with distribution half-life of approximately 1.4 hours and mean terminal half-life (t1/2) of 21 hours. The t1/2 of Aranesp was approximately 3-fold longer than that of epoetin alfa when administered intravenously.Following subcutaneous administration of Aranesp to patients with CKD (receiving or not receiving dialysis), absorption was slow and Cmax occurred at 48 hours (range: 12 to 72 hours). In patients with CKD receiving dialysis, the average t1/2 was 46 hours (range: 12 to 89 hours), and in patients with CKD not receiving dialysis, the average t1/2 was 70 hours (range: 35 to 139 hours). Aranesp apparent clearance was approximately 1.4 times faster on average in patients receiving dialysis compared to patients not receiving dialysis. The bioavailability of Aranesp in patients with CKD receiving dialysis after subcutaneous administration was 37% (range: 30% to 50%).Pediatric Patients with CKDAranesp pharmacokinetics was evaluated in 12 pediatric patients (age to 16 years) with CKD receiving or not receiving dialysis in one study (n=12). In phase pharmacokinetic study, following single intravenous or subcutaneous Aranesp dose, Cmax and t1/2 were similar to those obtained in adult patients with CKD on dialysis. Additionally, following single subcutaneous dose, the average bioavailability was 54% (range: 32% to 70%), which was higher than that obtained in adult patients with CKD on dialysis.Adult Patients with CancerFollowing the first subcutaneous dose of 6.75 mcg/kg (equivalent to 500 mcg for 74-kg patient) in patients with cancer, the mean t1/2 was 74 hours (range: 24 to 144 hours) and Cmax was observed at 71 hours (range: 28 to 120 hours). When administered on once every week schedule, 48-hour postdose Aranesp levels after the fourth dose were similar to those after the first dose.Over the dose range of 0.45 to 4.5 mcg/kg Aranesp administered intravenously or subcutaneously on once weekly schedule and 4.5 to 15 mcg/kg administered subcutaneously on once every week schedule, systemic exposure was approximately proportional to dose. No evidence of accumulation was observed beyond an expected less than 2-fold increase in blood levels when compared to the initial dose.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postmarketing use of Aranesp.Because postmarketing reporting of adverse reactions is voluntary and from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Seizures see Warnings and Precautions 5.4 ] Pure Red Cell Aplasia see Warnings and Precautions 5.6 ] Serious Allergic Reactions see Warnings and Precautions 5.7 ] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )] Seizures see Warnings and Precautions 5.4 ] Pure Red Cell Aplasia see Warnings and Precautions 5.6 ] Serious Allergic Reactions see Warnings and Precautions 5.7 ] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited available data on Aranesp use in pregnant women are insufficient to determine drug-associated risk of major birth defects or miscarriage. In animal reproductive and developmental toxicity studies, Aranesp increased early post-implantation loss at doses approximating the clinical recommended starting doses see Data ]. Consider the benefits and risks of Aranesp for the mother and possible risks to the fetus when prescribing Aranesp to pregnant woman.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.DataAnimal DataWhen Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days to 15) and rabbits (gestational days to 18), there was no evidence of embryofetal toxicity or other adverse outcomes at the intravenous doses tested, up to 20 mcg/kg/day. This animal dose level of 20 mcg/kg/day is approximately 20-fold higher than the clinical recommended starting dose, depending on the patients treatment indication. Slightly reduced fetal weights were observed when rat and rabbit mothers received doses of mcg/kg or more, causing exaggerated pharmacological effects in both the rat and rabbit dams. This dose of mcg/kg is near the clinical recommended starting dose. While no adverse effects on uterine implantation occurred in animals, in rat fertility study, there was an increase in early post-implantation loss at doses equal to or greater than 0.5 mcg/kg, administered times weekly. It is not clear whether the increased post-implantation loss reflects drug effect on the uterine environment or on the conceptus. No significant placental transfer of Aranesp was observed in rats; placental transfer was not evaluated in rabbits.In peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation (day 6) throughout pregnancy and lactation (day 23). The lowest dose tested, 0.5 mcg/kg, did not cause fetal toxicity; this dose is approximately equivalent to the clinical recommended starting dose. At maternal doses of 2.5 mcg/kg and higher, pups had decreased fetal body weights, which correlated with slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Aranesp related effects were apparent for their offspring (F2 generation fetuses).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 1801 patients with CKD in clinical studies of Aranesp, 44% were age 65 and over, while 17% were age 75 and over. Of the 873 patients in clinical studies receiving Aranesp and concomitant cancer chemotherapy, 45% were age 65 and over, while 14% were age 75 and over. No differences in safety or efficacy were observed between older and younger patients.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions 5.1 )] Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer [see Warnings and Precautions 5.2 )] Hypertension [see Warnings and Precautions 5.3 )] Seizures [see Warnings and Precautions 5.4 )] Pure Red Cell Aplasia [see Warnings and Precautions 5.6 )] Serious Allergic Reactions [see Warnings and Precautions 5.7 )] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )] Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions 5.1 )] Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer [see Warnings and Precautions 5.2 )] Hypertension [see Warnings and Precautions 5.3 )] Seizures [see Warnings and Precautions 5.4 )] Pure Red Cell Aplasia [see Warnings and Precautions 5.6 )] Serious Allergic Reactions [see Warnings and Precautions 5.7 )] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )] Patients with CKD: Adverse reactions in >= 10% of Aranesp-treated patients in clinical studies were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension (6.1). Patients with Cancer Receiving Chemotherapy: Adverse reactions in >= 1% of Aranesp-treated patients in clinical studies were abdominal pain, edema, and thrombovascular events (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Patients with CKD: Adverse reactions in >= 10% of Aranesp-treated patients in clinical studies were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension (6.1). Patients with Cancer Receiving Chemotherapy: Adverse reactions in >= 1% of Aranesp-treated patients in clinical studies were abdominal pain, edema, and thrombovascular events (6.1).. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.Patients with Chronic Kidney DiseaseAdult PatientsAdverse reactions were determined based on pooled data from randomized, active-controlled studies of Aranesp with total of 1357 patients (Aranesp 766, epoetin alfa 591). The median duration of exposure for patients receiving Aranesp was 340 days, with 580 patients exposed for greater than months and 360 patients exposed for greater than year. The median (25th, 75th percentiles) weight-adjusted dose of Aranesp was 0.50 mcg/kg (0.32, 0.81). The median (range) age for patients administered Aranesp was 62 years (18 to 88). In the Aranesp group, 55% were male, 72% were white, 83% were receiving dialysis, and 17% were not receiving dialysis.Table lists adverse reactions occurring in >= 5% of patients treated with Aranesp.Table 5. Adverse Reactions Occurring in >= 5% of Patients with CKDAdverse ReactionPatients Treated with Aranesp (n 766)Hypertension31%Dyspnea17%Peripheral edema17%Cough12%Procedural hypotension10%Angina pectoris 8%Vascular access complications 8%Fluid overload 7%Rash/Erythema 5%Arteriovenous graft thrombosis 5%Rates of adverse reactions with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these studies. Pediatric PatientsAdverse reactions were determined based on pooled data from randomized, controlled trials [see Clinical Studies 14.1 )]. In one study, Aranesp was administered to 81 pediatric patients with CKD who had stable hemoglobin concentrations while previously receiving epoetin alfa. In second study, Aranesp was administered to 114 anemic pediatric patients with CKD receiving or not receiving dialysis for initial treatment of anemia. In these studies, the most frequently reported serious adverse reactions with Aranesp were hypertension and convulsions. The most commonly reported adverse reactions were hypertension, injection site pain, rash, and convulsions. Aranesp administration was discontinued because of injection site pain in patients and hypertension in patients.Patients with Cancer Receiving ChemotherapyAdverse reactions were based on data from randomized, double-blind, placebo-controlled study of Aranesp in 597 patients (Aranesp 301, placebo 296) with extensive stage small cell lung cancer (SCLC) receiving platinum-based chemotherapy. All patients were white, 64% were male, and the median age was 61 years (range: 28 to 82 years); 25% of the study population were from North America, Western Europe, and Australia. Patients received Aranesp at dose of 300 mcg or placebo weekly for weeks then every weeks for total of 24 weeks, and the median duration of exposure was 19 weeks (range: to 26 weeks).Adverse reactions were also based on data from randomized, double-blind, placebo-controlled studies, including the SCLC study described above, that enrolled 2112 patients (Aranesp 1203, placebo 909) with non-myeloid malignancies. Most patients were white (95%), male (52%), and the median age was 63 years (range: 18 to 91 years); 73% of the study population were from North America, Western Europe, and Australia. Dosing and schedules varied by study from once weekly to once every weeks, and the median duration of exposure was 12 weeks (range: to 27 weeks).Table 6. Thrombovascular Adverse Reactions in Patients Receiving ChemotherapySCLC StudyAll Placebo-controlled StudiesAdverse ReactionAranesp(n 301)Placebo(n 296)Aranesp(n 2888)Placebo(n 1742)Thromboembolic Adverse Reactions, (%)25 (8.3%)13 (4.4%)147 (5.1%)64 (3.7%) Arterial9 (3%)3 (1%)33 (1.1%)11 (0.6%) Myocardial infarction5 (1.7%)018 (0.6%)5 (0.3%) Venous16 (5.3%)10 (3.4%)118 (4.1%)55 (3.2%) Pulmonary embolism5 (1.7%)3 (1%)43 (1.5%)14 (0.8%) Cerebrovascular disorders14 (4.7%)9 (3%)38 (1.3%)23 (1.3%) Cerebrovascular disorders encompasses CNS hemorrhages and cerebrovascular accidents (ischemic and hemorrhagic). Events in this category may also be included under thromboembolic adverse reactions. In addition to the thrombovascular adverse reactions, abdominal pain and edema occurred at higher incidence in patients taking Aranesp compared to patients on placebo. Among all placebo-controlled studies, abdominal pain (13.2% vs. 9.4%) and edema (12.8% vs. 9.7%) were reported more frequently in patients receiving Aranesp compared to the placebo group. In the SCLC study the incidence of abdominal pain (10.3% vs. 3.4%) and edema (5.6% vs. 5.1%) in the Aranesp-treated patients compared to those receiving placebo.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postmarketing use of Aranesp.Because postmarketing reporting of adverse reactions is voluntary and from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Seizures see Warnings and Precautions 5.4 ] Pure Red Cell Aplasia see Warnings and Precautions 5.6 ] Serious Allergic Reactions see Warnings and Precautions 5.7 ] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )] Seizures see Warnings and Precautions 5.4 ] Pure Red Cell Aplasia see Warnings and Precautions 5.6 ] Serious Allergic Reactions see Warnings and Precautions 5.7 ] Severe Cutaneous Reactions [see Warnings and Precautions 5.8 )] 6.3 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity.In clinical studies, the percentage of patients with antibodies to Aranesp was examined using the Biacore(R) assay. Sera from 1501 patients with CKD and 1159 patients with cancer were tested. At baseline, prior to Aranesp treatment, binding antibodies were detected in 59 patients (4%) with CKD and 36 patients with cancer (3%). During Aranesp therapy (range: 22 to 177 weeks), follow-up sample was taken. One additional patient with CKD and additional patients with cancer developed antibodies capable of binding Aranesp. In two studies of pediatric patients with CKD aged 2-16, 20 of 111 patients with CKD (18%) receiving dialysis and of 69 patients (9%) not receiving dialysis had anti-ESA antibodies at baseline. During therapy, additional patients receiving dialysis and additional patients not receiving dialysis developed antibodies capable of binding Aranesp.None of the patients had antibodies capable of neutralizing the activity of Aranesp or endogenous erythropoietin at baseline or at end of study. No clinical sequelae consistent with PRCA were associated with the presence of these antibodies.The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.Neutralizing antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) see Warnings and Precautions 5.6 ].

BOXED WARNING SECTION.

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. Chronic Kidney Disease:In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin level of greater than 11 g/dL [see Warnings and Precautions (5.1)].No trial has identified hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks [see Dosage and Administration (2.2)].Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions (5.1)].Cancer:ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers [see Warnings and Precautions (5.2)].To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions [see Dosage and Administration (2.3)].Use ESAs only for anemia from myelosuppressive chemotherapy [see Indications and Usage (1.2)].ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [see Indications and Usage (1.3)].Discontinue following the completion of chemotherapy course [see Dosage and Administration (2.3)].. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin level of greater than 11 g/dL [see Warnings and Precautions (5.1)].. No trial has identified hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks [see Dosage and Administration (2.2)].. Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions (5.1)].. ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers [see Warnings and Precautions (5.2)].. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions [see Dosage and Administration (2.3)].. Use ESAs only for anemia from myelosuppressive chemotherapy [see Indications and Usage (1.2)].. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [see Indications and Usage (1.3)].. Discontinue following the completion of chemotherapy course [see Dosage and Administration (2.3)].. WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCESee full prescribing information for complete boxed warning.Chronic Kidney Disease:In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin level of greater than 11 g/dL (5.1).No trial has identified hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks (2.2).Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).Cancer:ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (5.2).Use the lowest dose to avoid RBC transfusions (2.3).Use ESAs only for anemia from myelosuppressive chemotherapy (1.2).ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3).Discontinue following the completion of chemotherapy course (2.3).. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin level of greater than 11 g/dL (5.1).. No trial has identified hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks (2.2).. Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).. ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (5.2).. Use the lowest dose to avoid RBC transfusions (2.3).. Use ESAs only for anemia from myelosuppressive chemotherapy (1.2).. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3).. Discontinue following the completion of chemotherapy course (2.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of Aranesp has not been evaluated in long-term animal studies. In toxicity studies of approximately months duration in rats and dogs, no tumorigenic or unexpected mitogenic responses were observed in any tissue type.Aranesp was not mutagenic or clastogenic under the conditions tested. Aranesp was negative in the in vitro bacterial reverse mutation assay, the in vitro mammalian cell gene mutation assay (using CHO cells), and in the in vivo mouse erythrocyte micronucleus assay.Aranesp increased the incidence of post-implantation losses in rats. Male and female rats received intravenous doses prior to and during mating; then females were treated times weekly during the first trimester of gestation (gestation days 1, 3, 5, and 7). No effect on reproductive performance, fertility, or sperm assessment parameters were detected at any of the doses evaluated (up to 10 mcg/kg, administered times weekly). The dose of 10 mcg/kg is more than 10-fold higher than the clinical recommended starting dose. An increase in post-implantation fetal loss was seen at doses equal to or greater than 0.5 mcg/kg, administered times weekly. The dose of 0.5 mcg/kg is approximately equivalent to the clinical recommended starting dose. Signs of exaggerated pharmacology were not observed in the mother receiving 0.5 mcg/kg or less, but were observed at 2.5 mcg/kg and higher.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.. 12.2 Pharmacodynamics. Increased hemoglobin levels are not generally observed until to weeks after initiating treatment with Aranesp.. 12.3 Pharmacokinetics. Adult Patients with CKDThe pharmacokinetics of Aranesp were studied in patients with CKD receiving or not receiving dialysis and patients with cancer receiving chemotherapy.Following intravenous administration of Aranesp to patients with CKD receiving dialysis, Aranesp serum concentration-time profiles were biphasic, with distribution half-life of approximately 1.4 hours and mean terminal half-life (t1/2) of 21 hours. The t1/2 of Aranesp was approximately 3-fold longer than that of epoetin alfa when administered intravenously.Following subcutaneous administration of Aranesp to patients with CKD (receiving or not receiving dialysis), absorption was slow and Cmax occurred at 48 hours (range: 12 to 72 hours). In patients with CKD receiving dialysis, the average t1/2 was 46 hours (range: 12 to 89 hours), and in patients with CKD not receiving dialysis, the average t1/2 was 70 hours (range: 35 to 139 hours). Aranesp apparent clearance was approximately 1.4 times faster on average in patients receiving dialysis compared to patients not receiving dialysis. The bioavailability of Aranesp in patients with CKD receiving dialysis after subcutaneous administration was 37% (range: 30% to 50%).Pediatric Patients with CKDAranesp pharmacokinetics was evaluated in 12 pediatric patients (age to 16 years) with CKD receiving or not receiving dialysis in one study (n=12). In phase pharmacokinetic study, following single intravenous or subcutaneous Aranesp dose, Cmax and t1/2 were similar to those obtained in adult patients with CKD on dialysis. Additionally, following single subcutaneous dose, the average bioavailability was 54% (range: 32% to 70%), which was higher than that obtained in adult patients with CKD on dialysis.Adult Patients with CancerFollowing the first subcutaneous dose of 6.75 mcg/kg (equivalent to 500 mcg for 74-kg patient) in patients with cancer, the mean t1/2 was 74 hours (range: 24 to 144 hours) and Cmax was observed at 71 hours (range: 28 to 120 hours). When administered on once every week schedule, 48-hour postdose Aranesp levels after the fourth dose were similar to those after the first dose.Over the dose range of 0.45 to 4.5 mcg/kg Aranesp administered intravenously or subcutaneously on once weekly schedule and 4.5 to 15 mcg/kg administered subcutaneously on once every week schedule, systemic exposure was approximately proportional to dose. No evidence of accumulation was observed beyond an expected less than 2-fold increase in blood levels when compared to the initial dose.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Clinical studies in the nephrology and chemotherapy-induced anemia clinical programs are designated with the prefixes N and C, respectively.. 14.1 Patients with Chronic Kidney Disease. Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusionIn early clinical studies conducted in patients with CKD on dialysis, ESAs have been shown to reduce the use of RBC transfusions. These studies enrolled patients with mean baseline hemoglobin levels of approximately 7.5 g/dL and ESAs were generally titrated to achieve hemoglobin level of approximately 12 g/dL. Fewer transfusions were given during the ESA treatment period when compared to pre-treatment interval.In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusionIn TREAT, randomized, double-blind trial of 4038 patients with CKD and type diabetes not on dialysis, post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered Aranesp to target hemoglobin of 13 g/dL compared to the control arm in which Aranesp was administered intermittently if hemoglobin concentration decreased to less than g/dL (15% versus 25%, respectively). In CHOIR, randomized open-label study of 1432 patients with CKD not on dialysis, use of an ESA to target higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile see Warnings and Precautions 5.1 )].ESA Effects on quality of lifeAranesp use has not been demonstrated in controlled clinical trials to improve quality of life, fatigue, or patient well-being.ESA Effects on rates of death and other serious cardiac adverse eventsThree randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type Diabetes and CKD [TREAT]) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish cardiovascular or renal benefit of targeting higher hemoglobin levels, in all studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions 5.1 )].Other ESA trialsThree studies (2 in adults and in pediatric patients) evaluated the safety and efficacy of the de novo use of Aranesp for the correction of anemia in patients with CKD, and studies (2 in adults and in pediatric patients) assessed the ability of Aranesp to maintain hemoglobin concentrations in patients with CKD who had been receiving other recombinant erythropoietins.De Novo Use of AranespAdult PatientsOnce Weekly Aranesp Starting DoseIn randomized, open-label studies, Aranesp or epoetin alfa was administered for the correction of anemia in patients with CKD who had not been receiving prior treatment with exogenous erythropoietin. Study N1 evaluated patients with CKD receiving dialysis; Study N2 evaluated patients not requiring dialysis. In both studies, the starting dose of Aranesp was 0.45 mcg/kg administered once weekly. The starting dose of epoetin alfa was 50 Units/kg times weekly in Study N1 and 50 Units/kg twice weekly in Study N2. When necessary, dosage adjustments were instituted to maintain hemoglobin in the study target range of 11 to 13 g/dL. (Note: The recommended hemoglobin target range is lower than the target range of these studies [s ee Dosage and Administration 2.2 ]). The primary efficacy endpoint was the proportion of patients who experienced at least 1 g/dL increase in hemoglobin concentration to level of at least 11 g/dL by 20 weeks (Study N1) or 24 weeks (Study N2). The studies were designed to assess the safety and effectiveness of Aranesp but not to support conclusions regarding comparisons between the products.In Study N1, the primary efficacy endpoint was achieved by 72% (95% CI: 62%, 81%) of the 90 patients treated with Aranesp and 84% (95% CI: 66%, 95%) of the 31 patients treated with epoetin alfa. The mean increase in hemoglobin over the initial weeks of Aranesp treatment was 1.1 g/dL (95% CI: 0.82 g/dL, 1.37 g/dL).In Study N2, the primary efficacy endpoint was achieved by 93% (95% CI: 87%, 97%) of the 129 patients treated with Aranesp and 92% (95% CI: 78%, 98%) of the 37 patients treated with epoetin alfa. The mean increase in hemoglobin from baseline through the initial weeks of Aranesp treatment was 1.38 g/dL (95% CI: 1.21 g/dL, 1.55 g/dL).Once Every Week Aranesp Starting DoseIn single-arm studies (N3 and N4), Aranesp was administered for the correction of anemia in patients with CKD not receiving dialysis. In both studies, the starting dose of Aranesp was 0.75 mcg/kg administered once every weeks.In Study N3 (study duration of 18 weeks), the hemoglobin goal (hemoglobin concentration >= 11 g/dL) was achieved by 92% (95% CI: 86%, 96%) of the 128 patients treated with Aranesp.In Study N4 (study duration of 24 weeks), the hemoglobin goal (hemoglobin concentration of 11 to 13 g/dL) was achieved by 85% (95% CI: 77%, 93%) of the 75 patients treated with Aranesp.Pediatric PatientsStudy N8 was double-blind, randomized, controlled study in 114 pediatric patients from to 18 years of age receiving darbepoetin alfa. In this study, pediatric patients with CKD receiving or not receiving dialysis who were anemic (hemoglobin [Hb] 10.0 g/dL) and not being treated with an erythropoiesis stimulating agent (ESA) received darbepoetin alfa weekly or once every weeks for the correction of anemia. The primary efficacy endpoint was proportion of patients having hemoglobin corrected to >= 10.0 g/dL at any time point after the first dose without receiving any red blood cell transfusions after randomization and within 90 days prior to the Hb measurement. For pediatric patients receiving QW dosing, 98% (95% CI: 91%-100%), had hemoglobin concentrations corrected to >= 10 g/dL. For those receiving Q2W dosing, 84% (95% CI: 72%-92%), had hemoglobin concentrations corrected to >= 10 g/dL. The study was designed to assess the safety and effectiveness of Aranesp but not to support conclusions regarding comparisons between the regimens.Conversion from Other Recombinant ErythropoietinsTwo studies of adults (N5 and N6) and study in pediatric patients (N7) were conducted in patients who had been receiving other recombinant erythropoietins for treatment of the anemia due to CKD. The studies compared the abilities of Aranesp and other erythropoietins to maintain hemoglobin concentrations within study target range of to 13 g/dL in adults and 10 to 12.5 g/dL in pediatric patients. (Note: The recommended hemoglobin target is lower than the target range of these studies [s ee Dosage and Administration 2.2 ]). Patients who had been receiving stable doses of other recombinant erythropoietins were randomized to Aranesp or continued with their prior erythropoietin at the previous dose and schedule. For patients randomized to Aranesp, the initial weekly dose was determined on the basis of the previous total weekly dose of recombinant erythropoietin.Adult PatientsStudy N5 was double-blind study in which 169 hemodialysis patients were randomized to treatment with Aranesp and 338 patients continued on epoetin alfa. Study N6 was an open-label study in which 347 patients were randomized to treatment with Aranesp and 175 patients were randomized to continue on epoetin alfa or epoetin beta. Of the patients randomized to Aranesp, 92% were receiving hemodialysis and 8% were receiving peritoneal dialysis.In Study N5, median weekly dose of 0.53 mcg/kg Aranesp (25th, 75th percentiles: 0.30, 0.93 mcg/kg) was required to maintain hemoglobin in the study target range. In Study N6, median weekly dose of 0.41 mcg/kg Aranesp (25th, 75th percentiles: 0.26, 0.65 mcg/kg) was required to maintain hemoglobin in the study target range.Pediatric PatientsStudy N7 was an open-label, randomized study conducted in the United States in pediatric patients from to 18 years of age with CKD receiving or not receiving dialysis. Eighty-one patients with hemoglobin concentrations that were stable on epoetin alfa received Aranesp (subcutaneously or intravenously), and 42 patients continued to receive epoetin alfa at the current dose, schedule, and route of administration. Patients received Aranesp once weekly if previously receiving epoetin alfa or times weekly or once every other week if previously receiving epoetin alfa weekly. median weekly dose of 0.41 mcg/kg Aranesp (25th, 75th percentiles: 0.25, 0.82 mcg/kg) was required to maintain hemoglobin in the study target range.. 14.2 Patients with Cancer Receiving Chemotherapy. The safety and efficacy of Aranesp was assessed in two multicenter, randomized studies in patients with anemia due to the effect of concomitantly administered cancer chemotherapy. Study C1 was randomized (1:1), placebo-controlled, double-blind, multinational study conducted in 314 patients where Aranesp was administered weekly. Study C2 was randomized (1:1), double-blind, double-dummy, active-controlled, multinational study conducted in 705 patients where Aranesp was administered either every week or every weeks. Efficacy was demonstrated by statistically significant reduction in the proportion of patients receiving RBC transfusions among patients who were on study therapy for more than 28 days.Study C1Study C1 was conducted in anemic patients (hemoglobin <= 11 g/dL) with non-small cell lung cancer or small cell lung cancer who were scheduled to receive at least 12 weeks of platinum-containing chemotherapy regimen. Randomization was stratified by tumor type and region (Australia vs. Canada vs. Europe). Patients received Aranesp 2.25 mcg/kg or placebo as weekly subcutaneous injection commencing on the first day of the chemotherapy cycle. Efficacy was determined by reduction in the proportion of patients who received RBC transfusions between week (day 29) and end of treatment period (12 weeks) in the subset of 297 randomized patients (148 Aranesp and 149 placebo) who were on-study at the beginning of study week 5. All 297 patients were white, 72% were male, 71% had non-small cell histology, and the median age was 62 years (range: 36 to 80). significantly lower proportion of patients in the Aranesp arm received RBC transfusions during week to the end of treatment compared to patients in the placebo arm (crude percentages: 26% vs. 50%; < 0.001, based on comparison of the difference in Kaplan-Meier proportions using the Cochran-Mantel-Haenszel strata-adjusted Chi-square test). Study C2Study C2 was conducted in anemic patients (hemoglobin 11 g/dL) with non-myeloid malignancies receiving chemotherapy. Randomization was stratified by region (Western vs. Central/Eastern Europe), tumor type (lung and gynecological vs. others), and baseline hemoglobin (< 10 vs. >= 10 g/dL); all patients received double-dummy placebo and either Aranesp 500 mcg every weeks or Aranesp 2.25 mcg/kg weekly subcutaneous injections for 15 weeks. Only patient was non-white, 55% were female, and the median age was 60 years (range: 20 to 86). One hundred seven patients (16%) had lung or gynecological cancer while 565 (84%) had other tumor types. In both treatment schedules, the dose was reduced by 40% of the previous dose if hemoglobin level increased by more than g/dL in 14-day period.Efficacy was determined by comparison of the proportion of patients who received at least RBC transfusion between week (day 29) and the end of treatment. Three hundred thirty-five patients in the every week dosing arm and 337 patients in the weekly dosing arm remained on study through or beyond day 29 and were evaluable for efficacy. Two hundred thirty-eight patients (71%) in the every 3-week arm and 261 patients (77%) patients in the weekly arm required dose reductions. Twenty-three percent (95% CI: 18%, 28%) of patients in the every 3-week treatment schedule and 28% (95% CI: 24%, 34%) in the weekly schedule received at least RBC transfusion. The observed difference in the RBC transfusion rates (every week minus weekly) was -5.8% (95% CI: -12.4%, 0.8%).Study C3Lack of Efficacy in Improving SurvivalStudy C3 was conducted in patients required to have hemoglobin concentration >= g/dL and <= 13 g/dL with previously untreated extensive-stage small cell lung cancer (SCLC) receiving platinum and etoposide chemotherapy. Randomization was stratified by region (Western Europe, Australia/North America, and rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or vs. 2), and lactate dehydrogenase (below vs. above the upper limit of normal). Patients were randomized to receive Aranesp (n 298) at dose of 300 mcg once weekly for the first weeks, followed by 300 mcg once every weeks for the remainder of the treatment period or placebo (n 298). This study was designed to detect prolongation in overall survival (from median of months to median of 12 months). For the final analysis, there was no evidence of improved survival (p 0.43, log-rank test).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Aranesp is contraindicated in patients with:Uncontrolled hypertension [see Warnings and Precautions 5.3 )]. Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs [see Warnings and Precautions 5.6 )]. Serious allergic reactions to Aranesp [see Warnings and Precautions 5.7 )].. Uncontrolled hypertension [see Warnings and Precautions 5.3 )]. Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs [see Warnings and Precautions 5.6 )]. Serious allergic reactions to Aranesp [see Warnings and Precautions 5.7 )].. Uncontrolled hypertension (4) Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs (4) Serious allergic reactions to Aranesp (4). Uncontrolled hypertension (4) Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs (4) Serious allergic reactions to Aranesp (4).

DESCRIPTION SECTION.

11 DESCRIPTION Darbepoetin alfa is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Darbepoetin alfa is 165-amino acid protein that differs from recombinant human erythropoietin in containing N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains chains. The additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons.Aranesp (darbepoetin alfa) injection is formulated as sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 +- 0.2).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Recommended starting dose for patients with CKD on dialysis (2.2):- 0.45 mcg/kg intravenously or subcutaneously weekly, or- 0.75 mcg/kg intravenously or subcutaneously every weeks- Intravenous route is recommended for patients on hemodialysis Recommended starting dose for patients with CKD not on dialysis (2.2):- 0.45 mcg/kg intravenously or subcutaneously at week intervals Recommended starting dose for pediatric patients with CKD:- 0.45 mcg/kg intravenously or subcutaneously weekly patients with CKD not on dialysis may also be initiated at 0.75 mcg/kg every weeks Recommended starting dose for patients with cancer on chemotherapy (2.3):- 2.25 mcg/kg subcutaneously weekly, or- 500 mcg subcutaneously every weeks. Recommended starting dose for patients with CKD on dialysis (2.2):- 0.45 mcg/kg intravenously or subcutaneously weekly, or- 0.75 mcg/kg intravenously or subcutaneously every weeks- Intravenous route is recommended for patients on hemodialysis Recommended starting dose for patients with CKD not on dialysis (2.2):- 0.45 mcg/kg intravenously or subcutaneously at week intervals Recommended starting dose for pediatric patients with CKD:- 0.45 mcg/kg intravenously or subcutaneously weekly patients with CKD not on dialysis may also be initiated at 0.75 mcg/kg every weeks Recommended starting dose for patients with cancer on chemotherapy (2.3):- 2.25 mcg/kg subcutaneously weekly, or- 500 mcg subcutaneously every weeks. 2.1 Important Dosing Information. Evaluation of Iron Stores and Nutritional FactorsEvaluate the iron status in all patients before and during treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Monitoring of Response to TherapyCorrect or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Aranesp. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.. 2.2 Patients with Chronic Kidney Disease. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin level of greater than 11 g/dL. No trial has identified hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions [see Warnings and Precautions 5.1 )]. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies 14 ].For all patients with CKDWhen initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. single hemoglobin excursion may not require dosing change.Do not increase the dose more frequently than once every weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments. If the hemoglobin rises rapidly (e.g., more than g/dL in any 2-week period), reduce the dose of Aranesp by 25% or more as needed to reduce rapid responses. For patients who do not respond adequately, if the hemoglobin has not increased by more than g/dL after weeks of therapy, increase the dose by 25%. For patients who do not respond adequately over 12-week escalation period, increasing the Aranesp dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Aranesp if responsiveness does not improve.For adult patients with CKD on dialysis:Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Aranesp. The recommended starting dose is 0.45 mcg/kg intravenously or subcutaneously as weekly injection or 0.75 mcg/kg once every weeks as appropriate. The intravenous route is recommended for patients on hemodialysis.For adult patients with CKD not on dialysis:Consider initiating Aranesp treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring RBC transfusion and, Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is goal. If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Aranesp, and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions. The recommended starting dose is 0.45 mcg/kg body weight intravenously or subcutaneously given once at four week intervals as appropriate.For pediatric patients with CKD:Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of Aranesp. The recommended starting dose for pediatric patients (less than 18 years) is 0.45 mcg/kg body weight administered as single subcutaneous or intravenous injection once weekly; patients not receiving dialysis may be initiated at dose of 0.75 mcg/kg once every weeks.When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions 5.1 and 5.2 ).Conversion from Epoetin alfa to Aranesp in patients with CKD on dialysisAranesp is administered less frequently than epoetin alfa.Administer Aranesp once weekly in patients who were receiving epoetin alfa to times weekly. Administer Aranesp once every weeks in patients who were receiving epoetin alfa once weekly.Estimate the starting weekly dose of Aranesp for adults and pediatric patients on the basis of the weekly epoetin alfa dose at the time of substitution (see Table 1). Maintain the route of administration (intravenous or subcutaneous injection).Table 1. Estimated Aranesp Starting Doses (mcg/week) for Patients with CKD on Dialysis Based on Previous Epoetin alfa Dose (Units/week)Previous Weekly Epoetin alfa Dose (Units/week)Aranesp Dose (mcg/week)AdultPediatric< 1,5006.251,500 to 2,4996.256.252,500 to 4,99912.5105,000 to 10,999252011,000 to 17,999404018,000 to 33,999606034,000 to 89,999100100>= 90,000200200For pediatric patients receiving weekly epoetin alfa dose of 1,500 Units/week, the available data are insufficient to determine an Aranesp conversion dose.Conversion from Epoetin alfa to Aranesp in patients with CKD not on dialysisRefer to Table 1. The dose conversion depicted in Table does not accurately estimate the once monthly dose of Aranesp.. Do not increase the dose more frequently than once every weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments. If the hemoglobin rises rapidly (e.g., more than g/dL in any 2-week period), reduce the dose of Aranesp by 25% or more as needed to reduce rapid responses. For patients who do not respond adequately, if the hemoglobin has not increased by more than g/dL after weeks of therapy, increase the dose by 25%. For patients who do not respond adequately over 12-week escalation period, increasing the Aranesp dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Aranesp if responsiveness does not improve.. Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Aranesp. The recommended starting dose is 0.45 mcg/kg intravenously or subcutaneously as weekly injection or 0.75 mcg/kg once every weeks as appropriate. The intravenous route is recommended for patients on hemodialysis.. Consider initiating Aranesp treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring RBC transfusion and, Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is goal. If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Aranesp, and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions. The recommended starting dose is 0.45 mcg/kg body weight intravenously or subcutaneously given once at four week intervals as appropriate.. Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of Aranesp. The recommended starting dose for pediatric patients (less than 18 years) is 0.45 mcg/kg body weight administered as single subcutaneous or intravenous injection once weekly; patients not receiving dialysis may be initiated at dose of 0.75 mcg/kg once every weeks.. Administer Aranesp once weekly in patients who were receiving epoetin alfa to times weekly. Administer Aranesp once every weeks in patients who were receiving epoetin alfa once weekly.. 2.3 Patients on Cancer Chemotherapy. Initiate Aranesp in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is minimum of two additional months of planned chemotherapy.Use the lowest dose of Aranesp necessary to avoid RBC transfusions.Recommended Starting DoseThe recommended starting dose and schedules are:2.25 mcg/kg every week subcutaneously until completion of chemotherapy course. 500 mcg every weeks subcutaneously until completion of chemotherapy course.Table 2. Dose AdjustmentDose AdjustmentWeekly ScheduleEvery Week ScheduleIf hemoglobin increases greater than g/dL in any 2-week period or If hemoglobin reaches level needed to avoid RBC transfusionReduce dose by 40%Reduce dose by 40%If hemoglobin exceeds level needed to avoid RBC transfusionWithhold dose until hemoglobin approaches level where RBC transfusions may be required Reinitiate at dose 40% below the previous dose Withhold dose until hemoglobin approaches level where RBC transfusions may be required Reinitiate at dose 40% below the previous doseIf hemoglobin increases by less than g/dL and remains below 10 g/dL after weeks of therapyIncrease dose to 4.5 mcg/kg/weekNo dose adjustmentIf there is no response as measured by hemoglobin levels or if RBC transfusions are still required after weeks of therapy Following completion of chemotherapy courseDiscontinue AranespDiscontinue Aranesp. 2.25 mcg/kg every week subcutaneously until completion of chemotherapy course. 500 mcg every weeks subcutaneously until completion of chemotherapy course.. If hemoglobin increases greater than g/dL in any 2-week period or If hemoglobin reaches level needed to avoid RBC transfusion. Withhold dose until hemoglobin approaches level where RBC transfusions may be required Reinitiate at dose 40% below the previous dose Withhold dose until hemoglobin approaches level where RBC transfusions may be required Reinitiate at dose 40% below the previous dose. If there is no response as measured by hemoglobin levels or if RBC transfusions are still required after weeks of therapy Following completion of chemotherapy course. 2.4 Preparation and Administration. The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Do not shake. Do not use Aranesp that has been shaken or frozen. Protect vials and prefilled syringes from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration. Discard unused portion of Aranesp in vials or prefilled syringes. Do not re-enter vial. Do not dilute Aranesp and do not administer in conjunction with other drug solutions. Self-Administration of the Prefilled SyringeTraining should aim to demonstrate to those patients and caregivers how to measure the dose of Aranesp, and the focus should be on ensuring that patient or caregiver can successfully perform all of the steps in the Instructions for Use for prefilled syringe. If patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of Aranesp or whether the patient would benefit from different Aranesp presentation. If patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the Aranesp prefilled syringe, use of the Aranesp vial may be considered.. The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Do not shake. Do not use Aranesp that has been shaken or frozen. Protect vials and prefilled syringes from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration. Discard unused portion of Aranesp in vials or prefilled syringes. Do not re-enter vial. Do not dilute Aranesp and do not administer in conjunction with other drug solutions. Training should aim to demonstrate to those patients and caregivers how to measure the dose of Aranesp, and the focus should be on ensuring that patient or caregiver can successfully perform all of the steps in the Instructions for Use for prefilled syringe. If patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of Aranesp or whether the patient would benefit from different Aranesp presentation. If patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the Aranesp prefilled syringe, use of the Aranesp vial may be considered.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Aranesp is clear, colorless solution available as:Single-dose vialsInjection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, 200 mcg and 300 mcgSingle-dose prefilled syringesInjection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL. Injection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, 200 mcg and 300 mcg. Injection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL. Single-dose vialsInjection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, 200 mcg and 300 mcg (3).Single-dose prefilled syringesInjection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL (3).. Injection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, 200 mcg and 300 mcg (3).. Injection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL (3).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Store at 36oF to 46oF (2oC to 8oC). Do not freeze.Do not shake. Protect from light; store Aranesp in the carton until use.Do not use Aranesp that has been shaken or frozen.Aranesp is clear, colorless solution available in the following packages:Single-dose Vial1 Vial/Pack, Packs/Case4 Vials/Pack, 10 Packs/Case200 mcg/1 mL(NDC 55513-006-01)25 mcg/1 mL(NDC 55513-002-04)300 mcg/1 mL(NDC 55513-110-01)40 mcg/1 mL(NDC 55513-003-04)60 mcg/1 mL(NDC 55513-004-04)100 mcg/1 mL(NDC 55513-005-04) Single-dose Prefilled Syringe (SingleJect(R)) with 27-gauge, 1/2 -inch needle with an UltraSafe(R) Needle Guard that is manually activated to cover the needle during disposal1 Syringe/Pack, Packs/Case4 Syringes/Pack, 10 Packs/Case200 mcg/0.4 mL(NDC 55513-028-01)10 mcg/0.4 mL(NDC 55513-098-04) 300 mcg/0.6 mL(NDC 55513-111-01)25 mcg/0.42 mL(NDC 55513-057-04) 500 mcg/1 mL(NDC 55513-032-01)40 mcg/0.4 mL(NDC 55513-021-04) 60 mcg/0.3 mL(NDC 55513-023-04) 100 mcg/0.5 mL(NDC 55513-025-04) 150 mcg/0.3 mL(NDC 55513-027-04).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Aranesp is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia due to:Chronic Kidney Disease (CKD) in patients on dialysis and patients not on dialysis (1.1). The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is minimum of two additional months of planned chemotherapy (1.2).Limitations of UseAranesp has not been shown to improve quality of life, fatigue, or patient well-being (1.3). Aranesp is not indicated for use:In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy (1.3). In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3). In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion (1.3). As substitute for RBC transfusions in patients who require immediate correction of anemia (1.3).. Chronic Kidney Disease (CKD) in patients on dialysis and patients not on dialysis (1.1). The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is minimum of two additional months of planned chemotherapy (1.2).. In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy (1.3). In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3). In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion (1.3). As substitute for RBC transfusions in patients who require immediate correction of anemia (1.3).. 1.1 Anemia Due to Chronic Kidney Disease. Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis.. 1.2 Anemia Due to Chemotherapy in Patients with Cancer. Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is minimum of two additional months of planned chemotherapy.. 1.3 Limitations of Use. Aranesp has not been shown to improve quality of life, fatigue, or patient well-being.Aranesp is not indicated for use:o In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.o In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.o In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.o As substitute for RBC transfusions in patients who require immediate correction of anemia.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).Review the steps for direct patient administration with patients and caregivers. Training should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of Aranesp prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if patient is on dose other than the entire prefilled syringe. If patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of Aranesp or whether the patient would benefit from different Aranesp presentation.Inform patients:Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression see Warnings and Precautions 5.1 and 5.2 )]. To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions. To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency. Of the need to have regular laboratory tests for hemoglobin. Instruct patients who self-administer Aranesp of the:Importance of following the Instructions for Use. Dangers of reusing needles, syringes, or unused portions of single-dose vials. Proper disposal of used syringes, needles, and unused vials, and of the full container. Importance of informing healthcare provider if difficulty occurs when measuring or administering partial doses from the Aranesp prefilled syringe. If difficulty occurs, use of other syringes or Aranesp vial may be considered.Aranesp(R) (darbepoetin alfa)Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 U.S.A.U.S. License Number 1080Patent: http://pat.amgen.com/aranesp/(C) 2001-2019 Amgen Inc. All rights reserved.UltraSafe(R) is registered trademark of Safety Syringes, Inc.1xxxxxx- v36. Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression see Warnings and Precautions 5.1 and 5.2 )]. To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions. To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency. Of the need to have regular laboratory tests for hemoglobin. Importance of following the Instructions for Use. Dangers of reusing needles, syringes, or unused portions of single-dose vials. Proper disposal of used syringes, needles, and unused vials, and of the full container. Importance of informing healthcare provider if difficulty occurs when measuring or administering partial doses from the Aranesp prefilled syringe. If difficulty occurs, use of other syringes or Aranesp vial may be considered.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using Aranesp to target hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1). Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2). Hypertension: Control hypertension prior to initiating and during treatment with Aranesp (5.3). Seizures: Aranesp increases the risk for seizures in patients with CKD (5.4). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.4). PRCA: If severe anemia and low reticulocyte count develop during Aranesp treatment, withhold Aranesp and evaluate for PRCA (5.6). Serious Allergic Reactions: Discontinue Aranesp and manage reactions (5.7). Severe Cutaneous Reactions: Discontinue Aranesp (5.8).. Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using Aranesp to target hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1). Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2). Hypertension: Control hypertension prior to initiating and during treatment with Aranesp (5.3). Seizures: Aranesp increases the risk for seizures in patients with CKD (5.4). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.4). PRCA: If severe anemia and low reticulocyte count develop during Aranesp treatment, withhold Aranesp and evaluate for PRCA (5.6). Serious Allergic Reactions: Discontinue Aranesp and manage reactions (5.7). Severe Cutaneous Reactions: Discontinue Aranesp (5.8).. 5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism. In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 14 g/dL) to lower targets (9 11.3 g/dL), Aranesp and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. Using Aranesp to target hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies 14.1 )]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration 2.2 )]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. rate of hemoglobin rise of greater than g/dL over weeks may contribute to these risks. In controlled clinical trials of patients with cancer, Aranesp and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.The design and overall results of the large trials comparing higher and lower hemoglobin targets are shown in Table 3.Table 3. Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients with CKDNormal Hematocrit Study (NHS)(N 1265)CHOIR(N 1432)TREAT(N 4038)Time Period of Trial1993 to 19962003 to 20062004 to 2009PopulationAdult patients with CKD on hemodialysis with coexisting CHF or CAD, hematocrit 30 +- 3% on epoetin alfaAdult patients with CKD not on dialysis with hemoglobin 11 g/dL not previously administered epoetin alfaAdult patients with CKD not on dialysis with type II diabetes, hemoglobin <= 11 g/dLHemoglobin Target; Higher vs. Lower (g/dL)14.0 vs. 10.013.5 vs. 11.313.0 vs. >= 9.0Median (Q1, Q3) Achieved Hemoglobin level (g/dL)12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) 13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) Primary EndpointAll-cause mortality or non-fatal MIAll-cause mortality, MI, hospitalization for CHF, or strokeAll-cause mortality, MI, myocardial ischemia, heart failure, and strokeHazard Ratio or Relative Risk (95% CI)1.28 (1.06 1.56) 1.34 (1.03 1.74)1.05 (0.94 1.17)Adverse Outcome for Higher Target GroupAll-cause mortalityAll-cause mortalityStrokeHazard Ratio or Relative Risk (95% CI)1.27 (1.04 1.54)1.48 (0.97 2.27)1.92 (1.38 2.68)Patients with Chronic Kidney DiseaseNormal Hematocrit Study (NHS): prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that higher target hematocrit (Hct) would result in improved outcomes compared with lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to maintenance hemoglobin of either 14 +- g/dL or 10 +- g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to target hemoglobin of 14 g/dL than for the patients randomized to target hemoglobin of 10 g/dL. For all-cause mortality, the HR 1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to target hemoglobin of 14 g/dL.CHOIR: randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; = 0.03].TREAT: randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with CKD not on dialysis (eGFR of 20 60 mL/min), anemia (hemoglobin levels <= 11 g/dL), and type diabetes mellitus, patients were randomized to receive either Aranesp treatment or matching placebo. Placebo group patients also received Aranesp when their hemoglobin levels were below g/dL. The trial objectives were to demonstrate the benefit of Aranesp treatment of the anemia to target hemoglobin level of 13 g/dL, when compared to placebo group, by reducing the occurrence of either of two primary endpoints: (1) composite cardiovascular endpoint of all-cause mortality or specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with Aranesp treatment (see Table 3), but the risk of stroke was increased nearly two-fold in the Aranesp-treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; < 0.001. The relative risk of stroke was particularly high in patients with prior stroke: annualized stroke rate 5.2% in the Aranesp treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among Aranesp-treated subjects with past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.Patients with CancerAn increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.In randomized, placebo-controlled study (Study in Table [ see Warnings and Precautions 5.2 ]) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated higher mortality at months (8.7% vs. 3.4%) and higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; = 0.012).Patients Having SurgeryAranesp is not approved for reduction of RBC transfusions in patients scheduled for surgical procedures.An increased incidence of DVT in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated. In randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received epoetin alfa and standard of care (SOC) treatment (n 340) or SOC treatment alone (n 340). higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients experienced other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and [2.1%] in the SOC group).Increased mortality was observed in randomized, placebo-controlled study of epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all deaths were associated with thrombotic events.. In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 14 g/dL) to lower targets (9 11.3 g/dL), Aranesp and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. Using Aranesp to target hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies 14.1 )]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration 2.2 )]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. rate of hemoglobin rise of greater than g/dL over weeks may contribute to these risks. In controlled clinical trials of patients with cancer, Aranesp and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.. 5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer. ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 4). Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies and 7), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies and 9).Table 4. Randomized, Controlled Studies with Decreased Survival and/or Decreased Locoregional ControlStudy/Tumor/(n)HemoglobinTargetHemoglobin(Median;Q1, Q3)Primary EfficacyOutcomeAdverse Outcome forESA-containing ArmChemotherapyStudy 1Metastatic breast cancer(n 2098)<=12 g/dL+11.6 g/dL;10.7, 12.1 g/dLProgression-freesurvival (PFS)Decreased progression-free and overall survivalStudy 2Metastatic breast cancer (n 939)12-14 g/dL12.9 g/dL;12.2, 13.3 g/dL12-month overall survivalDecreased 12-month survivalStudy 3Lymphoid malignancy(n 344)13-15 g/dL (M)13-14 g/dL (F)11 g/dL;9.8, 12.1 g/dLProportion of patients achieving hemoglobin responseDecreased overall survivalStudy 4Early breast cancer(n 733)12.5-13 g/dL13.1 g/dL;12.5, 13.7 g/dLRelapse-free and overall survivalDecreased 3-year relapse-free and overall survival Study 5Cervical cancer(n 114)12-14 g/dL12.7 g/dL;12.1, 13.3 g/dLProgression-free and overall survival and locoregional controlDecreased 3-year progression-free and overall survival and locoregional controlRadiotherapy AloneStudy 6Head and neck cancer(n 351)>= 15 g/dL (M)>= 14 g/dL (F)Not availableLocoregional progression-free survivalDecreased 5-year locoregional progression-free and overall survivalStudy 7Head and neck cancer(n 522)14-15.5 g/dLNot availableLocoregional disease controlDecreased locoregional disease controlNo Chemotherapy or RadiotherapyStudy 8Non-small cell lung cancer(n 70)12-14 g/dLNot availableQuality of lifeDecreased overall survivalStudy 9Non-myeloid malignancy(n 989)12-13 g/dL10.6 g/dL;9.4, 11.8 g/dLRBC transfusionsDecreased overall survivalQ1 25th percentile Q3 75th percentile+This study did not include defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.Decreased Overall SurvivalStudy was described in the previous section see Warnings and Precautions 5.1 ]. Mortality at months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; = 0.012).Study was randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).Study was multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; = 0.04).Study was randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).Decreased Progression-free Survival and Overall SurvivalStudy was randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was non-inferiority study designed to rule out 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). At the final analysis, 1653 deaths were reported (79.8% of subjects in the epoetin alfa plus SOC group and 77.8% of subjects in the SOC group). Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).Study was randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. final analysis was performed after median follow-up of approximately years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.Study was randomized, open-label, controlled study that enrolled 114 of planned 460 patients with cervical cancer receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).Study was randomized, placebo-controlled study in 351 patients with head and neck cancer where epoetin beta or placebo was administered to achieve target hemoglobins >= 14 and >= 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; = 0.02).Decreased Locoregional ControlStudy was randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; = 0.08).Non-inferiority for Overall Survival and Progression-free SurvivalIn randomized, double-blind, placebo-controlled study to demonstrate non-inferiority of overall survival for Aranesp compared to placebo in patients with anemia receiving chemotherapy for the treatment of advanced stage non-small cell lung cancer (NSCLC), total of 2549 adult patients who were expected to receive >= cycles of myelosuppressive chemotherapy and with hemoglobin (Hb) <= 11.0 g/dL, were randomized 2:1 to Aranesp or placebo and treated to maximum Hb of 12 g/dL.Non-inferiority of Aranesp versus placebo was shown for overall survival (OS) and progression-free survival (PFS). The study was designed to rule out 15% risk increase. The median OS for Aranesp versus placebo was 9.5 and 9.3 months, respectively (stratified hazard ratio 0.92; 95% CI: 0.84-1.01). The median PFS was 4.4 and 4.2 months, respectively (stratified hazard ratio 0.96; 95% CI: 0.87-1.05). Aranesp did not demonstrate superiority to placebo for OS or PFS. Thrombovascular events were more frequent with Aranesp than placebo group (5.3% Aranesp, 4.1% placebo). No new safety signals were identified [see Warnings and Precautions 5.1 )]. 5.3 Hypertension Aranesp is contraindicated in patients with uncontrolled hypertension. In Aranesp clinical studies, approximately 40% of patients with CKD required initiation or intensification of antihypertensive therapy during the early phase of treatment. Hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Aranesp.Appropriately control hypertension prior to initiation of and during treatment with Aranesp. Reduce or withhold Aranesp if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions see Patient Counseling Information 17 ].. 5.4 Seizures. Aranesp increases the risk of seizures in patients with CKD. During the first several months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.. 5.5 Lack or Loss of Hemoglobin Response to Aranesp. For lack or loss of hemoglobin response to Aranesp, initiate search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA see Warnings and Precautions 5.6 ]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Aranesp therapy [see Dosage and Administration 2.2 )].. 5.6 Pure Red Cell Aplasia. Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis treatment (an indication for which Aranesp is not approved).If severe anemia and low reticulocyte count develop during treatment with Aranesp, withhold Aranesp and evaluate patients for neutralizing antibodies to erythropoietin. Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies. Permanently discontinue Aranesp in patients who develop PRCA following treatment with Aranesp or other erythropoietin protein drugs. Do not switch patients to other ESAs.. 5.7 Serious Allergic Reactions. Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp. Immediately and permanently discontinue Aranesp and administer appropriate therapy if serious allergic or anaphylactic reaction occurs.. 5.8 Severe Cutaneous Reactions. Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Aranesp) in the post-marketing setting. Discontinue Aranesp therapy immediately if severe cutaneous reaction, such as SJS/TEN, is suspected. 5.9 Dialysis Management. Patients may require adjustments in their dialysis prescriptions after initiation of Aranesp. Patients receiving Aranesp may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.