Darbepoetin alfa

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.

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 a minimum of two additional months of planned chemotherapy.

Limitations Of Use

Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use:

• In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
• In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
• In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
• As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Included as part of the PRECAUTIONS section.

Darbepoetin alfa 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. 

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see WARNINGS AND PRECAUTIONS]
• Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• PRCA [see WARNINGS AND PRECAUTIONS]
• Serious allergic reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Disease

Adverse reactions were determined based on pooled data from 5 randomized, active-controlled studies of Aranesp with a 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 6 months and 360 patients exposed for greater than 1 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 5 lists adverse reactions occurring in ≥ 5% of patients treated with Aranesp.

Table 5: Adverse Reactions Occurring in ≥ 5% of Patients with CKD

Rates of adverse reactions with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these studies.

Adverse reactions were determined based on pooled data from 2 randomized, controlled trials [see Clinical Studies]. In one study, Aranesp was administered to 81 pediatric patients with CKD who had stable hemoglobin concentrations while previously receiving epoetin alfa. In a 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 2 patients and hypertension in 3 patients.

Patients With Cancer Receiving Chemotherapy

Adverse reactions were based on data from a 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 a dose of 300 mcg or placebo weekly for 4 weeks then ever y 3 weeks for a total of 24 weeks, and the median duration of exposure was 19 weeks (range: 1 to 26 weeks).

Adverse reactions were also based on data from 7 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 4 weeks, and the median duration of exposure was 12 weeks (range: 1 to 27 weeks).

Table 6: Thrombovascular Adverse Reactions in Patients Receiving Chemotherapy

In addition to the thrombovascular adverse reactions, abdominal pain and edema occurred at a 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.

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during postmarketing use of Aranesp:

• Seizures [see WARNINGS AND PRECAUTIONS]
• PRCA [see WARNINGS AND PRECAUTIONS]
• Serious allergic reactions [see WARNINGS AND PRECAUTIONS]

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. 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].

In clinical studies, the percentage of patients with antibodies to Aranesp was examined using the Biacore® 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), a follow-up sample was taken. One additional patient with CKD and 8 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 6 of 69 patients (9%) not receiving dialysis had anti-ESA antibodies at baseline. During therapy, 4 additional patients receiving dialysis and 4 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.

Read the entire FDA prescribing information for Aranesp (Darbepoetin Alfa)

Other drugs may interact with darbepoetin alfa, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

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

• Has pharmacologic actions identical to those of endogenous erythropoietin;1 2 10 interacts with progenitor stem cells to increase red cell production.1

• Erythropoietin deficiency is the primary cause of anemia in patients with CKD.1

• In patients with cancer receiving concomitant chemotherapy, etiology of anemia is multifactorial.1

• Darbepoetin Alfa Polysorbate
• Erythropoiesis-Stimulating Agent (ESA)
• Erythropoiesis-Stimulating Protein
• NESP
• Novel Erythropoiesis-Stimulating Protein

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection [preservative free]:

Aranesp (Albumin Free): 25 mcg/mL (1 mL); 40 mcg/mL (1 mL); 60 mcg/mL (1 mL); 100 mcg/mL (1 mL); 150 mcg/0.75 mL (0.75 mL [DSC]); 200 mcg/mL (1 mL); 300 mcg/mL (1 mL) [albumin free; contains mouse (murine) and/or hamster protein, polysorbate 80]

Solution Prefilled Syringe, Injection [preservative free]:

Aranesp (Albumin Free): 10 mcg/0.4 mL (0.4 mL); 25 mcg/0.42 mL (0.42 mL); 40 mcg/0.4 mL (0.4 mL); 60 mcg/0.3 mL (0.3 mL); 100 mcg/0.5 mL (0.5 mL); 150 mcg/0.3 mL (0.3 mL); 200 mcg/0.4 mL (0.4 mL); 300 mcg/0.6 mL (0.6 mL); 500 mcg/mL (1 mL) [albumin free; contains mouse (murine) and/or hamster protein, polysorbate 80]

>10%:

Cardiovascular: Hypertension (31%), peripheral edema (17%), edema (6% to 13%)

Gastrointestinal: Abdominal pain (10% to 13%)

Respiratory: Dyspnea (17%), cough (12%)

1% to 10%:

Cardiovascular: Angina pectoris, hypotension, myocardial infarction, pulmonary embolism, thromboembolism, thrombosis of hemodialysis vascular access, thrombosis of vascular graft (arteriovenous)

Central nervous system: Cerebrovascular disease

Dermatologic: Erythema, skin rash

Endocrine & metabolic: Hypervolemia

<1% (Limited to important or life-threatening): Anaphylaxis, anemia (associated with neutralizing antibodies; severe; with or without other cytopenias), angioedema, bronchospasm, cerebrovascular accident, hypersensitivity reaction, hypertensive encephalopathy, pure red cell aplasia, seizure, tumor growth (progression/recurrence; cancer patients), urticaria

Concerns related to adverse effects:

• Cardiovascular events: [US Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis, and mortality in clinical studies when administered to target hemoglobin levels >11 g/dL (and provide no additional benefit); a rapid rise in hemoglobin (>1 g/dL over 2 weeks) may also contribute to these risks.

• Hypersensitivity: Potentially serious allergic reactions have been reported (rarely), including anaphylactic reactions, angioedema, bronchospasm, rash, and urticaria. Discontinue immediately (and permanently) in patients who experience serious allergic/anaphylactic reactions.

• Pure red cell aplasia (PRCA): Cases of severe anemia and PRCA (with or without other cytopenias) have been reported, predominantly in patients with chronic kidney disease receiving SubQ darbepoetin alfa (the intravenous [IV] route is preferred for hemodialysis patients). Cases have also been reported in patients with hepatitis C who were receiving ESAs, interferon, and ribavirin. Patients with a sudden loss of response to darbepoetin alfa (with severe anemia and a low reticulocyte count) should be evaluated for PRCA with associated neutralizing antibodies to erythropoietin; discontinue treatment (permanently) in patients with PRCA secondary to neutralizing antibodies to erythropoietin. Antibodies may cross-react; do not switch to another ESA in patients who develop antibody-mediated anemia.

Disease-related concerns:

• Cancer patients: [US Boxed Warning]: A shortened overall survival and/or increased risk of time to tumor progression or recurrence has been reported in studies with breast, cervical, head and neck, lymphoid, and non-small cell lung cancer patients. It is of note that in most of these studies, patients received ESAs to a target hemoglobin of ≥12 g/dL; although risk has not been excluded when dosed to achieve a target hemoglobin of <12 g/dL. [US Boxed Warnings]: To decrease these risks, and risk of cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions. Use ESAs in cancer patients only for the treatment of anemia related to concurrent myelosuppressive chemotherapy; discontinue ESA following completion of the chemotherapy course. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative. A dosage modification is appropriate if hemoglobin levels rise >1 g/dL per 2-week time period during treatment (Rizzo 2010). Use of ESAs has been associated with an increased risk of venous thromboembolism (VTE) without a reduction in transfusions in patients >65 years of age with cancer (Hershman 2009). Improved anemia symptoms, quality of life, fatigue, or well-being have not been demonstrated in controlled clinical trials.

• Chronic kidney disease patients: [US Boxed Warning]: An increased risk of death, serious cardiovascular events, and stroke was reported in chronic kidney disease patients administered ESAs to target hemoglobin levels >11 g/dL; use the lowest dose sufficient to reduce the need for RBC transfusions. An optimal target hemoglobin level, dose, or dosing strategy to reduce these risks has not been identified in clinical trials. Hemoglobin rising >1 g/dL in a 2-week period may contribute to the risk (dosage reduction recommended). Chronic kidney disease patients who exhibit an inadequate hemoglobin response to ESA therapy may be at a higher risk for cardiovascular events and mortality compared to other patients. ESA therapy may reduce dialysis efficacy (due to increase in red blood cells and decrease in plasma volume); adjustments in dialysis parameters may be needed. Chronic kidney disease patients not requiring dialysis may have a better response to darbepoetin alfa and may require lower doses. Patients treated with ESAs may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.

• Hypertension: Use with caution in patients with a history of hypertension; use is contraindicated in patients with uncontrolled hypertension. An excessive rate of rise of hemoglobin may be associated with exacerbation of hypertension; decrease the darbepoetin alfa dose if the hemoglobin increase exceeds 1 g/dL in any 2-week period. Blood pressure should be controlled prior to start of therapy and monitored closely throughout treatment. Hypertensive encephalopathy has been reported with patients receiving erythropoietic therapy.

• Perisurgical patients: Increased mortality was observed in patients undergoing coronary artery bypass surgery who received epoetin; these deaths were associated with thrombotic events. An increased risk of deep vein thrombosis has been observed in patients treated with epoetin undergoing surgical orthopedic procedures. Darbepoetin alfa is not approved for reduction in allogeneic red blood cell transfusions in patients scheduled for surgical procedures.

• Seizures: The risk for seizures is increased with darbepoetin alfa use in patients with chronic kidney disease; use with caution in patients with a history of seizures. Monitor closely for neurologic symptoms during the first several months of therapy.

• Severe anemia or acute blood loss: Due to the delayed onset of erythropoiesis, darbepoetin alfa is not recommended for acute correction of severe anemia or as a substitute for emergency transfusion.

Dosage form specific issues:

• Latex: The packaging of some formulations may contain latex.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use:

- Oncology: The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) 2010 updates to the clinical practice guidelines for the use of ESAs in patients with cancer indicate that ESAs are appropriate when used according to the parameters identified within the Food and Drug Administration (FDA)–approved labeling for epoetin and darbepoetin alfa (Rizzo 2010). ESAs are an option for chemotherapy-associated anemia when the hemoglobin has fallen to <10 g/dL to decrease the need for red blood cell transfusions. ESAs should only be used in conjunction with concurrent chemotherapy. Although the FDA label now limits ESA use to the palliative setting, the ASCO/ASH guidelines suggest using clinical judgment in weighing risks versus benefits as formal outcomes studies of ESA use defined by intent of chemotherapy treatment have not been conducted.

- Cardiovascular disease: The American College of Physicians recommends against the use of ESAs in patients with mild to moderate anemia and heart failure or coronary heart disease (ACP [Qaseem 2013]). The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 Heart Failure Guidelines do not provide a clear recommendation on the use of ESAs in anemic heart failure patients. The effects of ESAs on quality of life measures, morbidity, and mortality are potentially modest and still unclear. The authors declined to provide an official recommendation regarding the use of ESAs pending the completion of ongoing randomized trials (ACCF/AHA [Yancy 2013]).

• Factors impairing erythropoiesis: Prior to treatment, correct or exclude deficiencies of iron, vitamin B12, and/or folate, as well as other factors that may impair erythropoiesis (inflammatory conditions, infections, bleeding). Poor response to therapy should prompt evaluation of potential factors impairing erythropoiesis, as well as possible malignant processes and hematologic disease (thalassemia, refractory anemia, myelodysplastic disorder), occult blood loss, hemolysis, osteitis fibrosa cystic, and/or bone marrow fibrosis.

• Iron supplementation: Prior to and during therapy, iron stores must be evaluated. Supplemental iron is recommended if serum ferritin <100 mcg/L or serum transferrin saturation <20%. Most patients with chronic kidney disease will require iron supplementation.

US BOXED WARNINGS:
-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, dose of this drug, or dosing strategy that does not increase these risks. Use the lowest dose of this drug sufficient to reduce the need for RBC transfusions.
-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. Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense this drug to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course.

Safety and efficacy have not been established in cancer patients younger than 18 years.

Consult WARNINGS section for additional precautions.

ANEMIA ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD):
Adult:
Initial dose: 0.45 mcg/kg IV or subcutaneously once a week or 0.75 mcg/kg once every 2 weeks as appropriate

Comments:
-Initiate treatment when hemoglobin is less than 10 g/dL.
-The intravenous route is recommended for patients on hemodialysis.

Pediatric (Less than 18 Years):
Initial dose: 0.45 mcg/kg IV or subcutaneously once a week

Comments: Initiate treatment when hemoglobin is less than 10 g/dL.

Administration advice: The manufacturer product information should be consulted.

Storage requirements:
-Refrigerate at 36 to 46F (2 to 8C). Do not freeze.
-Protect from light.

Reconstitution/preparation techniques:
-Do not dilute.
-Do not shake. Do not use this drug if it has been shaken or frozen.
-Allow this drug to reach room temperature before injecting.
-Discard unused portion in vials or prefilled syringes. Do not re-enter vial.

IV compatibility: Do not administer in conjunction with other drug solutions.

General:
-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.
-Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies.

Monitoring:
-Following treatment initiation and dose adjustments, monitor hemoglobin weekly until stable and sufficient to minimize need for RBC transfusion. Monitor at least monthly thereafter provided hemoglobin remains stable.
-Monitor patients closely for premonitory neurologic symptoms during the first several months following initiation of this drug.

Patient advice:
-Inform cancer patients that they must sign the patient-healthcare provider acknowledgment form before the start of each treatment course with this drug.
-Inform patients of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression.
-Advise patients of the importance of regular blood pressure monitoring and compliance with concomitant antihypertensive therapy and dietary restrictions.
-Advise patients to seek medical attention for new/different neurologic symptoms.
-Inform patients of the need to have regular laboratory tests for hemoglobin.