Aranesp

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Darbepoetin alfa can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use darbepoetin alfa. Seek emergency medical help if you have:

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs; or
• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, confusion, severe chest pain, shortness of breath, irregular heartbeats.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;
• unusual weakness or tiredness;
• a seizure (convulsions); or
• shortness of breath (even with mild exertion), swelling, rapid weight gain.

Common side effects may include:

• high blood pressure;
• cough, trouble breathing;
• stomach pain; or
• swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Darbepoetin alfa is injected under the skin, or into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Darbepoetin alfa is given every 1 to 4 weeks, depending on the condition you are treating. Follow your doctor's dosing instructions very carefully.

You may need frequent medical tests to be sure this medicine is not causing harmful effects. Your injections may be delayed based on the results of these tests.

If you need surgery, tell the surgeon ahead of time that you are using darbepoetin alfa. You may need to stop using the medicine for a short time.

You may need to take blood pressure medication while you are using darbepoetin alfa. Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Store in the refrigerator and protect from light. Do not freeze darbepoetin alfa, and throw away the medication if it has become frozen.

Do not shake the medicine. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use vial (bottle) or prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Call your doctor for instructions if you miss a dose of darbepoetin alfa.

Aranesp (darbepoetin alfa) is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Aranesp is a 165-amino acid protein that differs from recombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 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 is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 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).

Aranesp is a prescription erythropoietin medicine used to treat a lower than normal number of red blood cells (anemia) caused by chronic kidney disease or chemotherapy. 

• Amgen USA Inc.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Aranesp there are no specific foods that you must exclude from your diet when receiving Aranesp.

Tell your doctor about all your medical conditions, including if you:

• Have heart disease. 
• Have high blood pressure. 
• Have had a seizure (convulsion) or stroke. 
• Are allergic to latex.
• Have any other medical conditions.

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

If you take too much Aranesp call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Aranesp is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Absorption

Bioavailability

Approximately 37% (range 30–50%) or 54% (range 32–70%) in adult or pediatric patients, respectively, with CKD following sub-Q administration.1

Absorption is slow and rate limiting following sub-Q administration.1

Distribution

Extent

Not known whether darbepoetin alfa is distributed into milk.1

Elimination

Half-life

Following sub-Q administration: 49 hours (range: 27–89 hours) in adult patients with CKD.1

Pediatric patients (3–16 years of age) with CKD with or without dialysis following a single IV or sub-Q dose: Half-life similar to that in adults.1

Patients with cancer following a single sub-Q dose: 74 hours (range: 24–144 hours).1

Following IV administration: Distribution half-life is approximately 1.4 hours and terminal half-life is approximately 21 hours.1

Storage

Parenteral

2–8°C; protect from light.1 32 33 Do not freeze or shake.1 32 33 Discard vial or prefilled syringe that has been frozen or shaken.1 32

      Evaluation of Iron Stores and Nutritional Factors

Evaluate the iron status in all patients before and during treatment and maintain iron repletion.  Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Aranesp [see Warnings and Precautions (5.9)].

      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 a hemoglobin level of greater than 11 g/dL.  No trial has identified a 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 CKD

When 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.  A single hemoglobin excursion may not require a dosing change.

• Do not increase the dose more frequently than once every 4 weeks.  Decreases in dose can occur more frequently.  Avoid frequent dose adjustments.
  
• If the hemoglobin rises rapidly (e.g., more than 1 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 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
  
• For patients who do not respond adequately over a 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 a 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 a weekly injection or 0.75 mcg/kg once every 2 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 a RBC transfusion and, 
  ° Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a 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 a single subcutaneous or intravenous injection once weekly; patients not receiving dialysis may also be initiated at a dose of 0.75 mcg/kg once every 2 weeks.

When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.2).

Refer patients who self-administer Aranesp to the Instructions for Use [see Patient Counseling Information (17)].

Conversion from Epoetin alfa to Aranesp in patients with CKD on dialysis

Aranesp is administered less frequently than epoetin alfa.

• Administer Aranesp once weekly in patients who were receiving epoetin alfa 2 to 3 times weekly.
  
• Administer Aranesp once every 2 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).

*For pediatric patients receiving a 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 dialysis

Refer to Table 1. The dose conversion depicted in Table 1 does not accurately estimate the once monthly dose of Aranesp.

      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 a minimum of two additional months of planned chemotherapy.

Use the lowest dose of Aranesp necessary to avoid RBC transfusions.

Recommended Starting Dose

The recommended starting dose and schedules are:

• 2.25 mcg/kg every week subcutaneously until completion of a chemotherapy course.
  
• 500 mcg every 3 weeks subcutaneously until completion of a chemotherapy course.

      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 Syringe

• 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 a patient or caregiver can successfully perform all of the steps in the Instructions for Use for a prefilled syringe.  If a 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 a different Aranesp presentation.  If a 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.

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)].

      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 a 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. A rate of hemoglobin rise of greater than 1 g/dL over 2 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 3 large trials comparing higher and lower hemoglobin targets are shown in Table3.

Patients with Chronic Kidney Disease

Normal Hematocrit Study (NHS): A 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 a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 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 a target hemoglobin of 14 g/dL than for the patients randomized to a 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 a target hemoglobin of 14 g/dL.

CHOIR: A 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 a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL.  The trial was terminated early with adverse safety findings. A 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; p = 0.03].

TREAT: A 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 2 diabetes mellitus, patients were randomized to receive either Aranesp treatment or a matching placebo.  Placebo group patients also received Aranesp when their hemoglobin levels were below 9 g/dL.  The trial objectives were to demonstrate the benefit of Aranesp treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a 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 Table3), 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; p < 0.001. The relative risk of stroke was particularly high in patients with a 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 a 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 Cancer

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.

In a randomized, placebo-controlled study (Study 2 in Table 4 [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 a 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 a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 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; p = 0.012).

Patients Having Surgery

Aranesp 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 a 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).  A 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 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group).

Increased mortality was observed in a 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 4 deaths were associated with thrombotic events.

      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 6 and 7), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

*Q1 = 25th percentile

Q3 = 75th percentile

†This study did not include a 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 Survival

Study 2 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 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 4 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 2 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; p = 0.012).

Study 3 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy.  With a 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 8 was a 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), a 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; p = 0.04).

Study 9 was a 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 a 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 Survival

Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. 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. At the time of clinical data cutoff, 1337 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.2 months compared with 17.4 months in the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). 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%).

Study 4 was a 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. A final analysis was performed after a median follow-up of approximately 3 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 5 was a randomized, open-label, controlled study that enrolled 114 of a 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 3 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 3 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 6 was a 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; p = 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; p = 0.02).

Decreased Locoregional Control

Study 7 was a 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 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

      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)].

      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.

      Lack or Loss of Hemoglobin Response to Aranesp

For lack or loss of hemoglobin response to Aranesp, initiate a 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)].

      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 C 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.

      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 a serious allergic or anaphylactic reaction occurs.

      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.

        Laboratory Monitoring

Evaluate transferrin saturation and serum ferritin prior to and during Aranesp treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [see Dosage and Administration (2.1)]. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

      Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Aranesp use in pregnant women. In animal reproduction and developmental toxicity studies, Aranesp increased early post-implantation loss. Use Aranesp during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When Aranesp was administered intravenously to healthy pregnant rats and rabbits, 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 patient’s treatment indication. Slightly reduced fetal weights were observed when healthy rat and rabbit mothers received doses of 1 mcg/kg or more. This dose of 1 mcg/kg is near the clinical recommended starting dose.  While no adverse effects on uterine implantation occurred in animals, there was an increase in early post-implantation loss in animal fertility studies. It is not clear whether the increased post-implantation loss reflects a drug effect on the uterine environment or on the conceptus. No significant placental transfer of Aranesp was detected.

In a peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation throughout pregnancy and lactation. 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 a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation  [see Nonclinical Toxicology (13.3)].

Women who become pregnant during Aranesp treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program.  Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

      Nursing Mothers

It is not known whether Aranesp is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aranesp is administered to a nursing woman.

      Pediatric Use

Pediatric Patients with CKD

Aranesp safety and efficacy were similar between adults and pediatric patients with CKD 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 Cancer

The safety and efficacy of Aranesp in pediatric patients with cancer have not been established.

      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.

NDC 55513-025-04

Single-Dose Prefilled Syringes with 27 Gauge Needles

4 x 100 mcg/0.5 mL Prefilled Syringes

AMGEN ®

Aranesp ® SingleJect ®

(darbepoetin alfa)

recombinant

Albumin Free

100 mcg

100 mcg/0.5 mL

For Intravenous or Subcutaneous Use Only

Sterile Solution – No Preservative

Store at 2° to 8°C (36° to 46°F).

Do Not Freeze or Shake.  Protect from Light.

This Product Contains Dry Natural Rubber.

Rx Only

U.S. License No. 1080

©2012, 2016 Amgen Inc.

Manufactured by Amgen Inc. Thousand Oaks, CA 91320-1799 U.S.A.

NDC 55513-004-04

Single-Dose Vials

4 x 60 mcg/1 mL Single-Dose Vials

AMGEN ®

Aranesp ®

(darbepoetin alfa)

recombinant

Albumin Free

60 mcg

60 mcg/1 mL

For Intravenous or Subcutaneous Use Only

Sterile Solution – No Preservative

Store at 2° to 8°C (36° to 46°F).  Do Not Freeze or Shake.

Protect from Light.

Rx Only

U.S. License No. 1080

©2012, 2016 Amgen Inc.

Manufactured by Amgen Inc.

Thousand Oaks, CA 91320-1799 U.S.A.

Darbepoetin alfa is a man-made form of a protein that helps your body produce red blood cells. The amount of this protein in your body may be reduced when you have kidney failure or use certain medications. When fewer red blood cells are produced, you can develop a condition called anemia.

Darbepoetin alfa is used to treat anemia (a lack of red blood cells in the body).

Darbepoetin alfa may also be used for purposes not listed in this medication guide.

Your pharmacist can provide more information about darbepoetin alfa.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 7.02. Revision date: 2/26/2012.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

• Bone Marrow Aspiration and Biopsy
• Cancer
• Kidney Failure

Aranesp can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. Darbepoetin alfa may also shorten remission time or survival time in some people with certain types of cancer. Talk with your doctor about the risks and benefits of using Aranesp.

Before using Aranesp, tell your doctor if you have heart disease, congestive heart failure, high blood pressure, kidney disease, a blood cell or clotting disorder, cancer, a seizure disorder, a latex allergy, or a history of stroke, heart attack, or blood clots.

You should not use Aranesp if you have uncontrolled high blood pressure, or if you have ever had pure red cell aplasia (PRCA, a type of anemia) caused by using darbepoetin alfa or epoetin alfa (Epogen or Procrit).

Seek emergency medical help if you have symptoms of heart or circulation problems, such as chest pain or heavy feeling, pain spreading to the arm or shoulder, shortness of breath, slurred speech, or problems with vision or balance.

To be sure Aranesp is helping your condition, your blood may need to be tested often. Your blood pressure will also need to be checked. Visit your doctor regularly.

Contact your doctor if you feel light-headed or unusually weak or tired. These may be signs that your body has stopped responding to Aranesp.

You should not use Aranesp if you are allergic to darbepoetin alfa or epoetin alfa (Epogen or Procrit), or if you have:

• untreated or uncontrolled high blood pressure; or

• if you have ever had pure red cell aplasia (PRCA, a type of anemia) caused by using darbepoetin alfa or epoetin alfa.

Aranesp may shorten remission time in some people with head and neck cancer who are also being treated with radiation. Aranesp may also shorten survival time in certain people with breast cancer, non-small cell lung cancer, head and neck cancer, cervical cancer, or lymphoid cancer. Talk with your doctor about your individual risk.

To make sure Aranesp is safe for you, tell your doctor if you have:

• heart disease, high blood pressure;

• kidney disease (or if you are on dialysis);

• a history of stroke, heart attack, or blood clots;

• cancer;

• a seizure disorder; or

• if you are allergic to latex.

It is not known whether Aranesp will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether darbepoetin alfa passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding a baby.

Use Aranesp exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Aranesp is injected under the skin, or into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used. You must also know how to properly measure a full or partial dose of this medicine.

Aranesp is given every 1 to 4 weeks, depending on the condition you are treating. Follow your doctor's dosing instructions very carefully.

You may need frequent medical tests to be sure this medicine is not causing harmful effects. Your injections may be delayed based on the results of these tests.

If you need surgery, tell the surgeon ahead of time that you are using Aranesp. You may need to stop using the medicine for a short time.

Call your doctor if you feel weak, tired, light-headed, or short of breath, or if your skin looks pale. These may be signs that your body has stopped responding to Aranesp.

You may need to take blood pressure medication while you are using Aranesp. Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Store in the refrigerator and protect from light. Do not freeze Aranesp, and throw away the medication if it has become frozen.

Do not shake the medicine. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use Aranesp vial (bottle) or prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Animal studies have revealed evidence of fetolethality and fetotoxicity. There are no controlled data in human pregnancy. Women who become pregnant during treatment are encouraged to enroll in Amgen's Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN to enroll. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

AU and US: This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. UK: Caution is recommended. AU TGA pregnancy category: B3 US FDA pregnancy category: C

UK: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. AU and US: Caution is recommended. Excreted into human milk: Unknown Excreted into animal milk: Data not available

Darbepoetin alfa is biologically and immunologically indistinguishable from erythropoietin, a normal component of human milk. IV darbepoetin has been given safely to newborn infants in doses much larger than those expected to appear in breastmilk.