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Darbepoetin Alfa (Monograph)

Brand name: Aranesp
Drug class: Hematopoietic Agents
VA class: BL400
Chemical name: Erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine] (human)
Molecular formula: C800H1300N228O224S5
CAS number: 209810-58-2

Medically reviewed by Drugs.com on Apr 25, 2023. Written by ASHP.

Warning

    Risk of Increased Mortality and Serious Adverse Events
  • Increased risk of death, serious cardiovascular events, and stroke reported in patients with chronic kidney disease (CKD) receiving therapy with darbepoetin alfa or other erythropoiesis-stimulating agents (ESAs) targeted to hemoglobin concentrations >11 g/dL in controlled clinical studies.

  • No trial has identified a hemoglobin target, ESA dosage, or dosing strategy that does not increase these risks.

  • ESA therapy shortened overall survival and/or increased risk of tumor progression or recurrence in some studies in patients with breast, non-small cell lung, head and neck, lymphoid, or cervical cancers.

  • To decrease these risks and risk of serious cardiovascular and thromboembolic events in anemic patients with cancer, use lowest ESA dosage sufficient to avoid RBC transfusion.

  • Use ESAs in cancer patients only for treatment of anemia caused by concomitant myelosuppressive chemotherapy.

  • ESAs not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure of the underlying malignancy.

  • Discontinue ESAs following completion of a course of chemotherapy.

Introduction

Biosynthetic (recombinant DNA origin) form of the glycoprotein hormone erythropoietin, a hematopoietic agent that principally affects erythropoiesis.

Uses for Darbepoetin Alfa

Anemia of Chronic Kidney Disease

Treatment of anemia associated with CKD in adult and pediatric patients who currently are undergoing hemodialysis or peritoneal dialysis therapy, as well as those who do not yet require maintenance dialysis (predialysis patients).

Some evidence suggests once-weekly darbepoetin alfa has similar safety and efficacy as equivalent doses of epoetin alfa given 2 or 3 times weekly in patients with CKD who are undergoing hemodialysis or peritoneal dialysis. In addition, administration of darbepoetin alfa once every other week appears to have similar efficacy as equivalent doses of sub-Q epoetin alfa administered once weekly.

Not intended for patients with CKD who require acute correction of severe anemia; do not use as a substitute for emergency transfusion.

Not established that ESAs improve quality of life, fatigue, or patient well-being.

The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends addressing all correctable causes of anemia prior to starting ESA therapy and weighting the potential benefits and risks of ESAs for each patient where therapy is considered. Individualization of therapy when using ESAs is stressed throughout this guideline, as individual patient responses to treatment may differ. The guideline does not specify a preferred ESA and suggests that “copy” versions of ESAs should only be those which have been designated a true biosimilar. The Kidney Disease Outcomes Quality Initiative (KDOQI) US Commentary on the 2012 KDIGO guideline states that for maintenance therapy, KDOQI supports a lower limit of goal hemoglobin of 11 g/dL.

Chemotherapy-induced Anemia in Patients with Nonmyeloid Malignancies

Treatment of chemotherapy-induced anemia in adult patients with nonmyeloid malignancies in whom chemotherapy is planned for at least 2 additional months; used to decrease the need for blood transfusions in such patients.

ESAs not indicated in patients with chemotherapy-induced anemia when the anticipated outcome is cure of the underlying malignancy. ESAs not shown to improve outcomes of cancer chemotherapy (e.g., in terms of greater tumor shrinkage, delayed tumor progression, increased survival). Not established that ESAs improve quality of life, fatigue, or patient well-being.

Not intended for patients who require acute correction of severe anemia; do not use as a substitute for emergency transfusion.

The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) published a joint guideline that provides recommendations for use of ESAs in patients with cancer. Per ASCO/ASH, ESAs and their biosimilars may be offered to patients with chemotherapy-induced anemia whose cancer treatment is not curative in intent and whose hemoglobin is <10 g/dL. The guideline’s Expert Panel considers epoetin alfa and beta, darbepoetin, and biosimilar epoetin alfa to be equivalent with respect to effectiveness and safety. In patients with nonmyeloid hematologic malignancies who are receiving concurrent myelosuppressive chemotherapy, hematologic response to cancer treatment should be observed before considering therapy with ESAs; particular caution should be exercised in the use of ESAs in patients with an increased risk of thromboembolic complications.

Anemia of Prematurity

Therapy with ESAs (epoetin alfa or darbepoetin alfa) has been evaluated in the treatment of anemia of prematurity [off-label], a condition in premature neonates that is due to impaired production of erythropoietin after birth, which is more pronounced in preterm infants who are already born with lower hematocrit compared to term infants.

Sickle Cell Anemia

Therapy with ESAs may be useful for delayed hemolytic transfusion reaction (DHTR) in patients with sickle cell disease [off-label]. The 2020 ASH guidelines recommend ESAs with or without IV iron as supportive care for all patients with DHTR. A 2014 Expert Panel Report from the Department of Health and Human Services acknowledges data supporting ESAs for DHTR. Neither guideline gives preference to a specific ESA product.

Myelodysplastic Syndrome

Therapy with ESAs may be useful for patients with myelodysplastic syndrome [off-label]. ASCO and ASH published a joint guideline that provides recommendations for use of ESAs in patients with cancer. Patients with nonchemotherapy-associated anemia should generally not be offered ESAs, with the exception of patients with lower risk myelodysplastic syndromes and a serum erythropoietin level ≤500 units/L. The guideline does not give preference to a specific ESA product for this use.

Hypoxic-ischemic Encephalopathy

Therapy with ESAs (epoetin alfa or darbepoetin alfa) may be useful for infants with hypoxic-ischemic encephalopathy (HIE) [off-label].

Bloodless Medicine

Therapy with ESAs may be useful to improve the efficiency and production of RBCs and limit blood loss in patients who refuse or are unable to receive allogeneic blood or blood products [off-label].

Darbepoetin Alfa Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Other General Considerations

Administration

Administer by IV or sub-Q injection.

IV or Sub-Q Administration

Do not expose to light, shake, or freeze prior to use. Do not dilute injection further prior to administration.

Do not administer in conjunction with other drug solutions.

Discard any unused portions of drug in the vials or prefilled syringes; do not re-enter vials.

The needle cover of the prefilled syringe contains natural latex proteins in the form of dry natural rubber (latex). Individuals sensitive to latex should not handle the needle cover due to the potential for allergic reactions.

May be self-administered in a home-care setting by patients if they are judged competent to do so by their clinician. For sub-Q injection using a vial and a disposable syringe or prefilled syringe, inject into the outer area of the upper arms, abdomen (except the 2-inch area around the navel), front of middle thighs, or upper outer areas of the buttocks. Do not inject into areas where skin is tender, bruised, red, or hard, or has scars or stretch marks.

The manufacturer recommends IV administration in patients with CKD undergoing hemodialysis.

When switching from epoetin alfa to darbepoetin alfa, administer darbepoetin alfa by the same route of administration (IV or sub-Q) that epoetin alfa was administered. Administer darbepoetin alfa once weekly if epoetin alfa was administered 2 or 3 times weekly. Administer darbepoetin alfa once every 2 weeks if epoetin alfa was administered once weekly. Administer first dose of darbepoetin alfa in place of epoetin alfa at the time of the next scheduled dose.

Dosage

Pediatric Patients

Anemia of Chronic Kidney Disease
IV or Sub-Q

Pediatric patients one month of age and older on dialysis: Initially, 0.45 mcg/kg administered IV or sub-Q once weekly; IV administration recommended in patients undergoing hemodialysis. Patients not on dialysis: Initially, 0.75 mcg/kg administered IV or sub-Q once every 2 weeks as appropriate. Initiate therapy when hemoglobin concentration <10 g/dL. Reduce or interrupt therapy if hemoglobin approaches or exceeds 12 g/dL.

In pediatric patients currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends an initial dosage based on the weekly epoetin alfa dosage at the time of substitution; see Table 1.

The dosage recommendations in Table 1 can be used for converting patients with CKD not on dialysis; however, this dose conversion does not accurately estimate the once monthly dose of darbepoetin.

For pediatric patients receiving a weekly epoetin alfa dosage of <1500 units/week, data are insufficient to determine initial darbepoetin alfa dosage.

Table 1. Estimated Darbepoetin Starting Doses (mcg/week) for Pediatric Patients with CKD on Dialysis Based on Previous Epoetin Dose (units/week)1

Previous Weekly Epoetin Alfa Dosage (units/week)

Initial Weekly Darbepoetin Alfa Dosage (mcg/week)

<1500

----

1500–2499

6.25

2500–4999

10

5000–10,999

20

11,000–17,999

40

18,000–33,999

60

34,000–89,999

100

≥90,000

200

Adjust subsequent dosage based on hemoglobin concentrations. Consider rate of hemoglobin increase or decrease, ESA responsiveness, and hemoglobin variability when determining whether a dosage adjustment is needed; a single hemoglobin excursion may not require a dosage change.

Monitor hemoglobin concentration at least weekly following initiation of therapy and after each dosage adjustment until stable, then monitor at least monthly.

If hemoglobin concentration increases by >1 g/dL in any 2-week period, reduce dosage by 25% or more as necessary to reduce risk of a rapid response.

If hemoglobin has not increased by >1 g/dL after 4 weeks of therapy, increase dosage by 25%. Do not increase dosage more frequently than once every 4 weeks. If an adequate response not obtained within 12 weeks, evaluate for other causes of anemia. Further dosage increases not likely to improve patient response and may increase risks of therapy; use lowest dosage sufficient to reduce need for RBC transfusions and discontinue drug if responsiveness does not improve.

Adults

Anemia of Chronic Kidney Disease
IV or Sub-Q

Patients on dialysis: Initially, 0.45 mcg/kg administered IV or sub-Q once weekly or 0.75 mcg/kg administered IV or sub-Q once every 2 weeks as appropriate; IV administration recommended in patients undergoing hemodialysis. Initiate therapy when hemoglobin concentration <10 g/dL. Reduce or interrupt therapy if hemoglobin approaches or exceeds 11 g/dL.

Patients not on dialysis: Initially, 0.45 mcg/kg administered IV or sub-Q once every 4 weeks as appropriate. Consider initiating therapy when hemoglobin <10 g/dL and the following 2 conditions apply: rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion, and a goal of therapy is to reduce risk of alloimmunization and/or other risks associated with RBC transfusions. Reduce or interrupt therapy if hemoglobin >10 g/dL.

Conversion of epoetin alfa therapy to darbepoetin alfa in CKD patients on dialysis: In patients currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends an initial dosage based on the weekly epoetin alfa dosage at the time of substitution (See Table 2).

The dosage recommendations in Table 2 can be used for converting patients with CKD not on dialysis; however, this dose conversion does not accurately estimate the once monthly dose of darbepoetin.

Table 2. Estimated Darbepoetin Starting Doses (mcg/week) for Patients with CKD on Dialysis Based on Previous Epoetin Dose (units/week)1

Previous Weekly Epoetin Alfa Dosage (units/week)

Initial Weekly Darbepoetin Alfa Dosage (mcg/week)

<1500

6.25

1500–2499

6.25

2500–4999

12.5

5000–10,999

25

11,000–17,999

40

18,000–33,999

60

34,000–89,999

100

≥90,000

200

Adjust subsequent dosage based on hemoglobin concentrations. Consider rate of hemoglobin increase or decrease, responsiveness to the ESA, and hemoglobin variability when determining whether a dosage adjustment is needed; a single hemoglobin excursion may not require a dosage change.

Monitor hemoglobin concentration at least weekly following initiation of therapy and after each dosage adjustment until stable, then monitor at least monthly.

If hemoglobin increases by >1 g/dL in any 2-week period, reduce dosage by 25% or more as necessary to reduce risk of a rapid response.

If hemoglobin has not increased by >1 g/dL after 4 weeks of therapy, increase dosage by 25%. Do not increase dosage more frequently than once every 4 weeks. If an adequate response not obtained within 12 weeks, evaluate for other causes of anemia. Further dosage increases not likely to improve patient response and may increase risks of therapy; use lowest dosage sufficient to reduce need for RBC transfusions and discontinue drug if responsiveness does not improve.

Anemia Due to Chemotherapy in Patients with Nonmyeloid Malignancies
Sub-Q

Initially, 2.25 mcg/kg once weekly.

Alternatively, 500 mcg once every 3 weeks.

Initiate only if hemoglobin concentration <10 g/dL and at least 2 additional months of chemotherapy is planned. Discontinue following completion of a chemotherapy course.

The manufacturer recommends the subsequent dose adjustments in Table 3 based on hemoglobin level and frequency of dosing:

Hgb: hemoglobin; RBC: red blood cell

Table 3: Dosage Adjustments for Patients on Cancer Chemotherapy1

Dose Adjustment

Weekly Schedule

Every 3 Week Schedule

If Hgb increase is >1 g/dL in any 2-week period, or

Decrease dose by 40%

Decrease dose by 40%

if Hgb reaches a level to avoid RBC transfusion

If Hgb exceeds a level needed to avoid RBC transfusion

Withhold dose until Hgb approaches a level where RBC transfusion may be required

Withhold dose until Hgb approaches a level where RBC transfusion may be required

Reinitiate at a dose 40% below previous dose

Reinitiate at a dose 40% below previous dose

If Hgb increases by < 1 g/dL and remains below 10 g/dL after 6 weeks of treatment

Increase dose to 4.5 mcg/kg/week

No dose adjustment needed

If no response, as measured by Hgb levels, or if RBC transfusions are required after 8 weeks of treatment

Discontinue darbepoetin alfa

Discontinue darbepoetin alfa

Following completion of chemotherapy course

Special Populations

Hepatic Impairment

No specific dosage recommendations in hepatic impairment.

Renal Impairment

No specific dosage recommendations in renal impairment.

Geriatric Patients

No clinically significant differences in pharmacokinetics, safety, or efficacy in patients 65 years of age or older. Increased sensitivity cannot be ruled out.

Cautions for Darbepoetin Alfa

Contraindications

Warnings/Precautions

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

Increased risk of death and serious cardiovascular events in patients with CKD receiving ESAs targeted to hemoglobin concentrations >11 g/dL. In controlled clinical studies comparing higher (13–14 g/dL) to lower (9–11.3 g/dL) hemoglobin targets, an increased risk of death, MI, stroke, CHF, hemodialysis vascular access thrombosis, and other thromboembolic events was observed in the higher target hemoglobin groups. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at greater risk for cardiovascular events and mortality. Increases in hemoglobin >1 g/dL during any 2-week period also may contribute to these risks.

Increased incidence of thromboembolic events, some serious and life-threatening, in cancer patients receiving darbepoetin alfa or other ESAs (epoetin alfa). Increased incidence of fatal thromboembolic/vascular events and overall mortality reported in women with metastatic breast cancer who received epoetin alfa targeted to a hemoglobin concentration of 12–14 g/dL.

Increased incidence of thromboembolism in patients undergoing surgical procedures without prophylactic anticoagulation and receiving another ESA, epoetin alfa, to reduce allogeneic RBC transfusion requirements. Darbepoetin alfa not FDA-labeled for reduction of allogeneic RBC transfusions in patients undergoing surgery.

Increased Mortality and/or Tumor Progression

Decreased overall survival observed in patients with non-small-cell lung cancer receiving only palliative radiation therapy or no active therapy and another ESA (epoetin alfa) targeted to a hemoglobin concentration of 12–14 g/dL.

A shortened time to tumor progression observed in patients with advanced head and neck cancer receiving radiation therapy alone and an ESA.

Increased risk of death in patients with cancer-related anemia who were not receiving cancer chemotherapy or radiation therapy while receiving darbepoetin alfa. ESAs are not FDA-labeled for use in patients with cancer-related anemia who are not receiving myelosuppressive chemotherapy.

Hypertension

Risk of new or worsening hypertension in patients with CKD, particularly during early phase of therapy. May require initiation of or increases in antihypertensive therapy.

Contraindicated in patients with uncontrolled hypertension; BP should be under control before initiation of therapy. Monitor and control BP during therapy. If BP becomes difficult to control, reduce dosage of or withhold darbepoetin alfa.

Seizures

Seizures and hypertensive encephalopathy reported; risk appears greater in patients with CKD. Monitor closely for premonitory neurologic symptoms during the first several months of therapy.

Lack or Loss of Hemoglobin Response

Evaluate patients who fail to respond or experience a loss of hemoglobin response for potential causative factors (e.g., iron deficiency, infection, inflammation, bleeding).

In the absence of another etiology, evaluate for evidence of PRCA and test for presence of antibodies to erythropoietins.

Pure Red Cell Aplasia

PRCA and severe anemia with or without other cytopenias in association with neutralizing antibodies to endogenous erythropoietin reported during postmarketing experience in a limited number of patients. PRCA occurred predominantly in patients with CKD receiving ESAs by sub-Q administration.

PRCA also reported in patients with hepatitis C virus (HCV) infection receiving ESAs for anemia related to hepatitis treatment.

Withhold therapy in any patient who develops severe anemia and low reticulocyte counts; evaluate for presence of neutralizing antibodies to erythropoietin. Contact the manufacturer (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies.

Discontinue permanently in any patient with PRCA. Do not switch to another ESA.

Serious Allergic Reactions

Risk of severe allergic reactions, including anaphylactic reactions, angioedema, respiratory symptoms, skin rash, and urticaria. If a serious hypersensitivity or anaphylactic reaction occurs, discontinue immediately and institute appropriate therapy; do not reinitiate.

Severe Cutaneous Reactions

In the post-marketing setting, blistering and skin exfoliation reactions that include erythema multiforme and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with darbepoetin and other ESAs. Discontinue treatment if a serious cutaneous reaction is suspected.

Dialysis Management

Patients undergoing dialysis may require adjustments in their dialysis prescriptions following initiation of darbepoetin alfa. Heparin anticoagulation requirements during hemodialysis may be increased.

Specific Populations

Pregnancy

Insufficient evidence to determine if darbepoetin alfa use in pregnancy causes birth defects or miscarriage.

In animal studies, darbepoetin increased early post-implantation loss when administered at equivalent starting doses. Consider the benefits and risks of darbepoetin for the mother and possible risks to the fetus when prescribing darbepoetin.

Lactation

Not known whether darbepoetin alfa is distributed into milk; use with caution in nursing women.

Pediatric Use

Safety and efficacy in pediatric patients with CKD receiving and not receiving dialysis have been established in patients 1 month to 16 years of age. No data are available in patients less than 1 month old. Safety and efficacy in the initial treatment of anemia of CKD, and when transitioning to darbepoetin alfa therapy from epoetin alfa similar between adult and pediatric patients.

Safety and efficacy in pediatric cancer patients not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Use with caution.

Common Adverse Effects

Adverse effects occurring in at least 10% of patients with CKD receiving darbepoetin alfa in clinical studies include hypertension, dyspnea, peripheral edema, cough, and procedural hypotension.

Adverse effects occurring in at least 1% of adults with cancer receiving chemotherapy and darbepoetin alfa in clinical studies include abdominal pain, edema, and thrombovascular events (myocardial infarction, pulmonary embolism, cerebrovascular accidents, CNS hemorrhage).

Drug Interactions

No formal drug interaction studies have been performed.

Darbepoetin Alfa Pharmacokinetics

Absorption

Bioavailability

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

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

Special Populations

Geriatric patients: No substantial differences in safety and efficacy in adults 65 years of age and older.

Distribution

Extent

Not known whether darbepoetin alfa is distributed into milk.

Elimination

Half-life

Following sub-Q administration: 46 hours (range: 12–89 hours) in adult patients with CKD receiving dialysis; 70 hours (range: 35–139 hours) in adult patients with CKD not receiving dialysis.

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.

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

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

Stability

Storage

Parenteral

Injection

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

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Darbepoetin Alfa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

10 mcg/0.4 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

25 mcg/0.42 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

25 mcg/mL

Aranesp (available as single-dose vials)

Amgen

40 mcg/0.4 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

40 mcg/mL

Aranesp (available as single-dose vials)

Amgen

60 mcg/0.3 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

60 mcg/mL

Aranesp (available as single-dose vials)

Amgen

100 mcg/0.5 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

100 mcg/mL

Aranesp (available as single-dose vials)

Amgen

150 mcg/0.3 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

200 mcg/0.4 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

200 mcg/mL

Aranesp (available as single-dose vials)

Amgen

300 mcg/0.6 mL

Aranesp (available as single-dose prefilled syringes)

Amgen

300 mcg/mL

Aranesp (available as single-dose vials)

Amgen

500 mcg/mL

Aranesp (available as single-dose prefilled syringes)

Amgen

AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 25, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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Frequently asked questions