Aranesp

Generic Name: Darbepoetin Alfa
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

Special Alerts:

[Posted 06/24/2011] ISSUE: FDA notified healthcare professionals that new, modified recommendations for more conservative dosing of Erythropoiesis-Stimulating Agents (ESAs) in patients with chronic kidney disease (CKD) have been approved to improve the safe use of these drugs. FDA has made these recommendations because of data showing increased risks of cardiovascular events with ESAs in this patient population. The new dosing recommendations are based on clinical trials showing that using ESAs to target a hemoglobin level of greater than 11 g/dL in patients with CKD provides no additional benefit than lower target levels, and increases the risk of experiencing serious adverse cardiovascular events, such as heart attack or stroke.

BACKGROUND: ESAs treat certain types of anemia by stimulating the bone marrow to produce red blood cells and by decreasing the need for blood transfusions. The manufacturer has revised the Boxed Warning, Warnings and Precautions, and Dosage and Administration sections of the labels for the ESAs to include this new information.

RECOMMENDATION: Healthcare professionals should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions in CKD patients against the increased risks for serious cardiovascular events, and should inform their patients of the current understanding of potential risks and benefits. Therapy should be individualized to the patient and the lowest possible ESA dose given to reduce the need for transfusions. See the Drug Safety Communication for additional information including a table of key trials and other supporting references. Treatment with ESAs in CKD was discussed at the Drug Safety and Risk Management Advisory Committee, held October 18, 2010. For summary minutes of that Advisory Committee, see the following link: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for darbepoetin to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of darbepoetin and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, Stroke, and Increased Risk of Tumor Progression or Recurrence


• 
  

  Increased risk of death, serious cardiovascular events, and stroke reported in patients with chronic renal failure (CRF) receiving therapy with darbepoetin alfa or other erythropoiesis-stimulating agents (ESAs) targeted to hemoglobin concentrations ≥13 g/dL in clinical studies.^{1 19 20 21 22 23 24 25 28 29 30 31 38 39 40 45 620 622} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions.)

  
  


• 
  

  Individualize dosing of ESAs in CRF patients to achieve and maintain hemoglobin concentrations within 10–12 g/dL.^{1 28 29}

  
  

  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.^{1 24 25 28 29 34 35 38 39 40 41 42 43 49} (See Increased Mortality and/or Tumor Progression under Cautions.)

  
  


• 
  

  To decrease these risks and risk of serious cardiovascular and thromboembolic events in anemic patients with cancer, titrate ESA dosage to lowest hemoglobin concentration sufficient to avoid RBC transfusion.^{1 20 21 22 23 24 25 28 29}

  
  


• 
  

  Darbepoetin alfa may be prescribed and/or dispensed to cancer patients only by clinicians and institutions enrolled in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program.^{1 619} (See Risk Management Plan under Dosage and Administration.)

  
  


• 
  

  Use ESAs in cancer patients only for treatment of anemia caused by concomitant myelosuppressive chemotherapy.^{1 24 25 28 29 38 39 40 41}

  
  


• 
  

  ESAs not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure of the underlying malignancy.^{1 28 29 54}

  
  


• 
  

  Discontinue ESAs following completion of a course of chemotherapy.^{1 28 29}

  
  

Introduction

Biosynthetic (recombinant DNA origin) form of the glycoprotein hormone erythropoietin, a hematopoietic agent that principally affects erythropoiesis.^{1 2 9 10}

Uses for Aranesp

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Anemia of Chronic Renal Failure

Treatment of anemia associated with CRF in patients who currently are undergoing hemodialysis or peritoneal dialysis therapy, as well as those who do not yet require maintenance dialysis (predialysis patients).^{13 4 5 9 13}

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 CRF who are undergoing hemodialysis or peritoneal dialysis.^{1 6 7 9 11 12} 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.^{11 58 59 60}

ESAs, including darbepoetin alfa, may increase risk for death and serious cardiovascular events when targeted to hemoglobin concentrations ≥13 g/dL.^{1 19 20 21 22 23 24 25 28 29 30 38 39 40 620 622} (See Boxed Warning.) FDA has issued public health advisories regarding risks with ESAs;^{19 20 21 22 23 24 25 38 39 40} FDA cautions that dosage of these drugs in patients with CRF should be individualized to achieve and maintain hemoglobin concentrations of 10–12 g/dL.^{1 28 29} Renal Physicians Association (RPA) states that the clinical standard of care in patients with chronic kidney disease or end-stage renal failure now advocated by the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) is use of lowest ESA dosage that will gradually increase target hemoglobin concentration to 11–12 g/dL and not exceed 13 g/dL.^{26 48 50} RPA advises consideration of individual patient risks and benefits and use of evidence-based guidelines in changing anemia management regimens to avoid unacceptably low hemoglobin concentrations in CRF patients.²⁶

Chemotherapy-induced Anemia in Patients with Nonmyeloid Malignancies

Treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies;¹ used to decrease the need for blood transfusions in patients receiving therapy with antineoplastic agents.^{1 14 62}

Correction of hemoglobin to concentrations >12 g/dL not recommended because of the risk of adverse effects, including death and serious and/or life-threatening cardiovascular events.^{19 20 21 22 23 24 25 28 29 30} (See Boxed Warning.)

ESAs not indicated in patients with chemotherapy-induced anemia when the anticipated outcome is cure of the underlying malignancy.^{1 54} ESAs do not improve outcomes of cancer chemotherapy (e.g., in terms of greater tumor shrinkage, delayed tumor progression, increased survival).^{1 24 25 34 35 38 39 40 43 44 49} Not established that ESAs improve health-related quality of life, including effects on fatigue, energy, or strength, in patients with chemotherapy-induced anemia.^{24 25}

Chronic Anemia Associated with Malignancy

Darbepoetin alfa and other ESAs not indicated for use in anemic patients with active malignant disease who are not receiving cancer chemotherapy†.^{1 28 29} ESAs shorten the time to death and/or tumor progression in such patients when therapy is targeted to hemoglobin concentrations >12 g/dL^{1 24 25 28 29}

Aranesp Dosage and Administration

General

• 
  

  Administer under the supervision of a health-care professional.¹ (See Advice to Patients.)

  
  


• 
  

  Monitor hemoglobin concentration twice weekly until stabilized during initiation of therapy and at regular intervals thereafter.¹ Following dosage adjustment, monitor hemoglobin concentrations weekly for ≥4 weeks until stabilized, then at regular intervals thereafter.¹ Titrate to the lowest dosage that will gradually increase hemoglobin to the lowest concentration sufficient to avoid red blood cell transfusion.^{1 9 19 22 24 25} Do not exceed a hemoglobin concentration of 12 g/dL or a rate of increase in hemoglobin concentration of 1 g/dL in any 2-week period.^{1 9 19 22 24 25}

  
  

Risk Management Plan

• 
  

  A required risk management plan (Risk Evaluation and Mitigation Strategy, REMS) has been developed for all ESAs.^{1 619}

  
  


• 
  

  A medication guide explaining the risks and benefits of ESA therapy must be distributed to and discussed with all patients receiving these drugs.^{55 619 621}

  
  


• 
  

  In addition, the APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program has been created to minimize risk of decreased survival and poor tumor response in cancer patients receiving ESAs.^{1 619} Clinicians and institutions must enroll in and comply with all requirements of the program (e.g., training module, signed acknowledgment of patient counseling) before they can prescribe and/or dispense ESAs to patients with cancer; participants must re-enroll every 3 years.^{1 619} For additional information or to enroll in the ESA APPRISE Oncology program, contact 866-284-8089 or visit www.esa-apprise.com.^{1 619}

  
  

Anemia of Chronic Renal Failure

• 
  

  Predialysis patients may be more responsive to hematopoietic effects; judicious monitoring of BP, hemoglobin, renal function, and fluid and electrolyte balance and lower maintenance dosages may be required compared with dialysis patients.¹

  
  


• 
  

  Appreciable changes in hemoglobin not evident for 2–6 weeks following any dosage adjustment; allow sufficient time (≥1 month) to determine response before adjusting dosage.¹

  
  


• 
  

  Maintenance dosage will be lower than initial dosage in many patients.¹ Some patients also may benefit from less frequent administration of maintenance doses (e.g., sub-Q administration once every 2 weeks).¹

  
  

Administration

Administer by IV or sub-Q injection.^{1 8 9}

IV or Sub-Q Administration

Do not expose to light or shake prior to use; vigorous shaking and exposure to light may physically denature the glycoprotein structure and inactivate the molecule.^{1 32}

Do not dilute injection further prior to administration.¹

Do not administer in the same syringe with other drug solutions.¹

Observe strict aseptic technique; drug contains no preservative.¹ Once dose has been withdrawn from the single-use vial, prefilled syringes, or autoinjection device, administer promptly and discard any unused portion of the solution or discard the device.^{1 13 32 33} Unused portions of vials and syringes should not be pooled.¹

Sub-Q injections are preferred by some clinicians for predialysis and peritoneal dialysis patients because of the lack of existing accessible IV sites in such patients.⁸

Darbepoetin alfa may be self-administered in a home-care setting by patients if they are judged competent to do so by their clinician.¹ For sub-Q injection using an autoinjection device (SureClick autoinjector), inject into front center of thighs, abdomen, or back of upper arms (only if caregiver is available to administer the injection).³² 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.³³ Rotate injection sites; do not inject into areas where skin is tender, bruised, red, or hard.^{32 33} Avoid injecting into areas with scars or stretch marks.^{32 33}

Before using the prefilled syringe, check to see that the needle cover is on and the yellow needle guard is covering the barrel of the syringe.³³ If the needle guard is covering the needle, discard the syringe.³³ Do not slide the needle guard over the needle cover before injection; the sliding motion will lock the needle guard prematurely.³³

Following administration from the prefilled syringe, activate the needle guard to prevent accidental needle sticks.^{1 33} To activate the needle guard, hold the finger grip of the syringe with one hand and grasp the needle guard with the other hand.³³ Slide the guard completely over the needle until the needle guard clicks into place.³³

Prior to use of the autoinjection device, remove the grey needle shield; do not recap the device with the needle shield.³² Place the open end of the autoinjection device at 90° to the injection site and unlock the safety needle cover by pushing the cover firmly against the skin.³² Press the red button at the top of the autoinjection device and release the thumb from the red button.³² Wait to hear a second click and verify that the inspection window on the side of the autoinjection device has changed from clear to yellow before lifting the device away from the skin.³²

Because the prefilled autoinjection device is designed to deliver the full contents, use such devices only for patients who need the full dose.¹

The manufacturer recommends IV administration in patients with CRF undergoing hemodialysis.¹

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.^{1 9} Administer darbepoetin alfa once weekly if epoetin alfa was administered 2 or 3 times weekly.^{1 9} Administer darbepoetin alfa once every 2 weeks if epoetin alfa was administered once weekly.^{1 9} Administer first dose of darbepoetin alfa in place of epoetin alfa at the time of the next scheduled dose.⁸

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

Anemia of Chronic Renal Failure

IV or Sub-Q

In pediatric patients >1 year of age currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends the following initial dosage of darbepoetin alfa based on the weekly epoetin alfa dosage at the time of substitution (See Table 1):¹

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

Table 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

Dosage adjustments should not be made more frequently than once a month.¹

If hemoglobin has increased by <1 g/dL during initial 4 weeks of therapy and iron stores are adequate, increase dosage by approximately 25% of the previous dosage.^{1 8 9} Dosage may be increased at intervals of ≥4 weeks until the lowest hemoglobin concentration that will avoid the need for blood transfusion (not to exceed 12 g/dL) is attained.^{1 9 24 25}

If hemoglobin concentration is increasing and approaching 12 g/dL, decrease dosage by approximately 25% of the previous dosage.^{1 9} If the hemoglobin concentration continues to increase, temporarily withhold therapy until hemoglobin concentration begins to decrease, at which point reinitiate therapy at a dosage approximately 25% below the previous dosage.^{1 9} If the hemoglobin concentration increases by >1 g/dL in any 2-week period, decrease dosage by approximately 25%.^{1 9}

Patients who fail to respond or maintain a response to dosages >1.5 mcg/kg per week may be resistant to the drug; failure or lack of response to darbepoetin alfa should be evaluated to determine causative factors.^{1 9} (See Lack or Loss of Response to Therapy under Cautions.)

Predialysis patients may require lower maintenance dosages compared with dialysis patients.¹

Adults

Anemia of Chronic Renal Failure

IV or Sub-Q

Initially, 0.45 mcg/kg administered as a single IV or sub-Q injection once weekly.^{1 9}

In patients currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends the following initial dosage of darbepoetin alfa based on the weekly epoetin alfa dosage at the time of substitution (See Table 2):^{1 9}

Table 2.

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

Dosage adjustments should not be made more frequently than once a month.¹

If hemoglobin has increased by <1 g/dL during initial 4 weeks of therapy and iron stores are adequate, increase dosage by approximately 25% of the previous dosage.^{1 8 9} Dosage may be increased at intervals of ≥4 weeks until the lowest hemoglobin concentration that will avoid the need for blood transfusion (not to exceed 12 g/dL) is attained.^{1 9 24 25}

If hemoglobin concentration is increasing and approaching 12 g/dL, decrease dose by approximately 25% of the previous dosage.^{1 9} If the hemoglobin concentration continues to increase, temporarily withhold therapy until hemoglobin concentration begins to decrease, at which point reinitiate therapy at a dosage approximately 25% below the previous dosage.^{1 9} If the hemoglobin concentration increases by >1 g/dL in any 2-week period, decrease dosage by approximately 25% of the previous dosage.^{1 9}

Patients who fail to respond or maintain a response to dosages >1.5 mcg/kg per week may be resistant to the drug; failure or lack of response to darbepoetin alfa should be evaluated to determine causative factors.^{1 9} (See Lack or Loss of Response to Therapy under Cautions.)

Predialysis patients may require lower maintenance dosages compared with dialysis patients.¹

Chemotherapy-induced anemia in Patients with Nonmyeloid Malignancies

Sub-Q

2.25 mcg/kg once weekly.¹

Alternatively, 500 mcg once every 3 weeks.¹

Weekly dosage regimen: If hemoglobin concentration increases by <1 g/dL during the initial 6 weeks of therapy, increase dosage up to 4.5 mcg/kg weekly.¹

Weekly or every 3 weeks dosage regimen: If hemoglobin concentration increases by >1 g/dL in any 2-week period or exceeds 11 g/dL, decrease dosage by approximately 40% of the previous dosage.¹

Weekly or every 3 weeks dosage regimen: If the hemoglobin concentration is >12 g/dL, withhold therapy until hemoglobin concentration decreases to 11 g/dL, at which point reinstitute at a dosage 40% below the previous dosage.¹

Cautions for Aranesp

Contraindications

• 
  

  Uncontrolled hypertension.^{1 33} (See Hypertension and Seizures under Cautions.)

  
  


• 
  

  Known hypersensitivity to darbepoetin alfa or any ingredient in the formulation.^{1 33}

  
  

Warnings/Precautions

Warnings

Increased Mortality and Cardiovascular and Thromboembolic Events

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased risk of death and serious cardiovascular events (MI, stroke, CHF, hemodialysis graft occlusion) in patients receiving ESAs targeted to hemoglobin concentrations >12 g/dL.^{1 19 20 21 22 23 24 25 30 31 55 620 622} Patients with CRF and an insufficient hemoglobin response to ESA therapy may be at greater risk for cardiovascular events and mortality than other patients.¹

Increased incidence of thrombotic events (pulmonary embolism, thromboembolism, thrombophlebitis [deep and/or superficial], thrombosis) in cancer patients receiving darbepoetin alfa or other ESAs (epoetin alfa).^{1 24 25 46}

Increased incidence of thromboembolism in patients undergoing surgical procedures without prophylactic anticoagulation and receiving another ESA, epoetin alfa, to reduce allogeneic RBC transfusion requirements†.^{1 24 25 28 29 47} Darbepoetin alfa not FDA-labeled for reduction of allogeneic RBC transfusions in patients undergoing surgery.¹

Increased mortality reported in hemodialysis patients receiving another ESA, epoetin alfa, with clinically evident cardiac disease treated to a target hemoglobin concentration of 14 g/dL compared with similar patients treated to a target hemoglobin concentration of 10 g/dL.¹ Reason for increased mortality not known; incidence of nonfatal MI, vascular access thrombosis, and all other thrombotic events higher in those treated to a target hemoglobin concentration of 14 g/dL.¹

Increased risk of stroke observed in patients with type 2 diabetes, anemia, and non-dialysis-dependent CRF receiving darbepoetin alfa targeted to a hemoglobin concentration of 13 g/dL.^{1 620 622}

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.^{1 24 25} (See Boxed Warning for cardiovascular and thromboembolic events in other patient populations.)

Correction of hemoglobin to concentrations above those currently recommended (i.e., 12 g/dL) may increase the risk of serious and life-threatening cardiovascular events.^{1 19 20 21 23 61} The manufacturer recommends that the target hemoglobin concentration not exceed 12 g/dL and the rate of rise of hemoglobin concentrations not exceed 1 g/dL in any 2-week period.¹ Guidelines for dosage and frequency of dosage adjustment should be followed closely.¹ (See Dosage and Administration.)

Increased Mortality and/or Tumor Progression

Shortened overall survival and increased incidence of death attributed to disease progression observed in women with metastatic breast cancer receiving cancer chemotherapy and ESAs targeted to hemoglobin concentration >12 g/dL.^{1 24 28 29} (See Boxed Warning.)

A shortened time to tumor progression was observed in patients with advanced head and neck cancer receiving radiation therapy and ESAs targeted to hemoglobin concentration >12 g/dL.^{1 24 28 29 34 35}

Increased risk of death in patients with cancer-related anemia who were not receiving cancer chemotherapy or radiation therapy† while receiving darbepoetin alfa.^{1 24 25 46} ESAs are not FDA-labeled for use in patients with cancer-related anemia who are not receiving myelosuppressive chemotherapy.^{1 24 25 38 39 40 41}

ESAs, including darbepoetin alfa, can only be prescribed and dispensed to cancer patients by authorized clinicians and institutions enrolled in the ESA APPRISE Oncology program.^{1 619} (See Risk Management Plan under Dosage and Administration and also see Boxed Warning.)

Hypertension and Seizures

BP may increase during treatment with darbepoetin alfa.¹ Use is contraindicated in patients with uncontrolled hypertension; BP should be under control before initiation of therapy.¹ Monitor and aggressively control BP, particularly during first several months of therapy.¹ If BP is difficult to control with antihypertensive therapy or dietary measures, reduce dosage of or withhold darbepoetin alfa.¹

Seizures and hypertensive encephalopathy reported in patients with CRF during treatment.¹ Monitor BP and neurologic status during the first several months of therapy.¹ Guidelines for dosage and frequency of dosage adjustment should be closely followed.¹ (See Dosage under Dosage and Administration.)

Pure Red Cell Aplasia

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.^{1 16 56 57} PRCA occurred predominantly in patients with CRF receiving darbepoetin alfa by sub-Q administration.^{1 16}

Antibody-induced PRCA also reported in patients with hepatitis C virus (HCV) infection receiving ESAs concomitantly with ribavirin and interferon alfa (nonconjugated or pegylated).^{1 56 57}

Investigate the etiology of any loss of response to therapy accompanied by severe anemia and low reticulocyte counts.^{1 16 56} If anti-erythropoietin antibody-associated anemia is suspected, withhold darbepoetin alfa and other ESAs.^{1 16 56} Contact the manufacturer (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies.^{1 16 56}

Discontinue therapy permanently in any patient with antibody-mediated anemia.^{1 16 56} Do not switch to other ESAs as antibodies may cross-react.^{1 16 56}

Potential for Viral Transmission

Theoretical risk of transmission of Creutzfeldt-Jakob disease (CJD) associated with darbepoetin alfa formulation containing albumin human; however, transmission of CJD or viral diseases to a human recipient via administration of albumin human has not been reported.¹

Sensitivity Reactions

Hypersensitivity Reactions

Potentially serious hypersensitivity reactions including rash and urticaria occur rarely.¹ Recurrence of manifestations following rechallenge has occurred, suggesting a causal relationship.¹ If a serious hypersensitivity or anaphylactic reaction occurs, discontinue immediately and institute appropriate and symptomatic care as indicated.¹

Latex Sensitivity

The needle cover of the prefilled syringe contains natural latex proteins in the form of dry natural rubber (latex).^{1 51 52 53} Individuals sensitive to latex should not handle the needle cover.^{1 51 52 53} Rarely, hypersensitivity reactions to natural latex proteins have been fatal.^{52 53}

General Precautions

Concomitant Diseases

Safety and efficacy of darbepoetin alfa not established in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia,⁸ thalassemia, porphyria).^{1 9} Use with caution in patients with epilepsy.¹

Lack or Loss of Response to Therapy

A lack of response or failure to maintain a hemoglobin response with usual dosages of darbepoetin alfa should prompt evaluation for potential causative factors (e.g., PRCA).¹

Depending on the clinical setting, underlying infections, inflammatory or malignant processes, osteitis fibrosa cystica,¹³ occult blood loss, hemolysis, severe aluminum toxicity, and bone marrow fibrosis may compromise erythropoietic response.¹ Deficiencies of folic acid or vitamin B₁₂ should be excluded or corrected prior to initiation of therapy.¹ In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietins.¹ (See Pure Red Cell Aplasia under Cautions.)

Patient Monitoring

To ensure effective erythropoiesis, evaluate iron stores in all patients prior to and periodically during therapy.^{1 8 9} Supplemental iron therapy is recommended for all patients whose serum ferritin concentration is <100 mg/L or whose serum transferrin saturation is <20%.^{1 8}

Patients with CRF: Evaluate hemoglobin concentrations weekly during initiation of therapy and at regular intervals thereafter.¹ Following dosage adjustment, monitor hemoglobin concentrations weekly for ≥4 weeks until stabilized, then at regular intervals thereafter.¹ Monitor hemoglobin concentrations carefully to ensure that hemoglobin does not exceed 12 g/dL.^{1 24 25 27}

Dialysis Management

May reduce dialysis efficiency; patients who are marginally dialyzed may require adjustments in dialysis parameters.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether darbepoetin alfa is distributed into milk;^{1 32} use with caution in nursing women.¹

Pediatric Use

Safety and efficacy in the initial treatment of anemia of CRF not established.¹ Safety and efficacy of transferring from another erythropoietin in patients >1 year of age with CRF similar to adults.¹ Safety and efficacy of transferring from another erythropoietin not established in pediatric patients <1 year of age.¹

Safety and efficacy in pediatric cancer patients not established.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Use with caution.⁸

Common Adverse Effects

Adult patients with CRF: Infection,¹ hypertension,¹ hypotension,¹ myalgia,¹ headache,¹ diarrhea.¹

Pediatric patients with CRF: Fever, headache, upper respiratory infection, hypertension, hypotension, injection site pain, cough.¹

Patients with cancer: Fatigue,¹ diarrhea,¹ edema,¹ fever.¹

Interactions for Aranesp

No formal drug interaction studies have been performed.¹

Aranesp Pharmacokinetics

Absorption

Bioavailability

Approximately 37% (range 30–50%) or 54% (range 32–70%) in adult or pediatric patients, respectively, with CRF 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 CRF.¹

Pediatric patients (3–16 years of age) with CRF 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

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.^{1 32 33} Do not freeze or shake.^{1 32 33} Discard autoinjection device, vial, or prefilled syringe that has been frozen, exposed to light, or improperly refrigerated.^{32 3} For a more comfortable sub-Q injection, refrigerated autoinjection device (SureClick autoinjector), vial, or prefilled syringe may be allowed to stand protected from light at room temperature for about 30 minutes prior to injection; do not warm autoinjection device.^{32 33}

Actions

• 
  

  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 CRF.¹

  
  


• 
  

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

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of informing patients about the increased risks of death, serious cardiovascular effects, thromboembolic events, and tumor progression in certain patient populations.^{1 32 33} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions and also see Boxed Warning.)

  
  


• 
  

  Provide a copy of the patient instructions for use and medication