Darbepoetin alfa (Aranesp) is synthetic form of erythropoietin with a three times longer half-life than epoitin alfa. It is used in the treatment of anemia in patients with chronic kidney disease and other chronic illnesses.

Indications of Darbepoetin alfa (Aranesp):

• Anemia due to chemotherapy in patients with cancer:

  • It is indicated for the treatment of anemia in patients with non-myeloid malignancies when anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of 2 additional months of planned chemotherapy.

• Anemia due to chronic kidney disease:

  • It is used for treating anemia due to chronic kidney disease, including patients on dialysis and patients not on dialysis.
  • Limitations of use:
    • Darbepoetin alfa has not demonstrated improved quality of life, fatigue, or well-being.
    • Darbepoetin alfa is not indicated for use under the following conditions:
      • Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy
      • Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative
      • Cancer patients receiving myelosuppressive chemotherapy when anemia can be managed by transfusion
      • As a substitute for red blood cell (RBC) transfusion in patients requiring immediate correction of anemia

• Off Label Use of Darbepoetin alfa in Adults:

  • Symptomatic anemia in myelodysplastic syndromes

Darbepoetin alpha dose in adults:

Note:

• Iron status should be checked in all patients before and during therapy.
• Supplemental iron should be given if serum ferritin is <100 ng/ml or serum transferrin saturation is <20% as per manufacturer.
• Most patients with CKD will require iron supplementation.

Darbepoetin alfa (Aranesp) dose in the treatment of anemia due to chronic kidney disease:

Dosing should be individualized and the lowest possible dose should be given to reduce the need for red blood cell transfusions.

• Chronic kidney disease patients on dialysis (IV route is preferred for hemodialysis patients.
• Treatment should be started when hemoglobin is <10 g/dl.
• Dose reduction or interruption should be done if hemoglobin approaches or exceeds 11 g/dl).
  • IV, SubQ: Initial:
    • 0.45 mcg/kg once weekly or 0.75 mcg/kg once every 2 weeks or conversion from epoetin alfa: Epoetin alfa doses of <1,500 to ≥90,000 units per week may be converted to darbepoetin alfa doses ranging from 6.25 to 200 mcg per week (see the adult column in the conversion table below).
• Chronic kidney disease patients not on dialysis (treatment should be started when hemoglobin is <10 g/dL;
  • use only if the rate of hemoglobin decline would likely result in RBC transfusion and desire is to reduce the risk of alloimmunization or other RBC transfusion-related risks.
  • Dose reduction or interruption should be done if hemoglobin exceeds 10 g/dl):
  • IV, SubQ: Initial:
    • 0.45 mcg/kg once every 4 weeks
• Dosage adjustments for chronic kidney disease patients (either on dialysis or not on dialysis):
  • Do not increase the dose more frequently than every 4 weeks (dose decreases may occur more frequently).
  • Dose reduction by 25% should be done if hemoglobin increases >1 g/dl in any 2-week period.
  • If hemoglobin does not increase by >1 g/dL after 4 weeks:
    • Increase dose by 25%.
  • Inadequate or lack of response: If adequate response is not achieved over 12 weeks, further increases are unlikely to be of benefit and may increase the risk for adverse events.
  • The lowest effective dose should be used to maintain a hemoglobin level sufficient to avoid RBC transfusions and evaluate the patient for other causes of anemia.
  • Therapy should be stopped if improvement cannot be seen.

Darbepoetin alfa (Aranesp) dose in the treatment of anemia due to chemotherapy in cancer patients:

Treatment should be started only if hemoglobin <10 g/dL and the anticipated duration of myelosuppressive chemotherapy is at least 2 additional months. The lowest effective dose should be given to maintain a hemoglobin level sufficient to avoid RBC transfusions. After completion of chemotherapy, therapy should be stopped.

• SubQ: Initial:
  • 2.25 mcg/kg once weekly or 500 mcg once every 3 weeks until completion of a chemotherapy course.

• Dosage adjustments:

  • Increase dose:
    • dose to 4.5 mcg/kg once weekly (no dosage adjustment if using every-3-week dosing) if hemoglobin does not increase by 1 g/dL and remains below 10 g/dl after initial 6 weeks (for patients receiving weekly therapy only).
  • If hemoglobin increases >1 g/dL in any 2-week period or hemoglobin reaches a level sufficient to avoid RBC transfusion, dose reduction by 40% should be done
  • If hemoglobin exceeds a level needed to avoid RBC transfusion, therapy should be withheld.
  • Treatment should be reinitiated with a 40% dose reduction when hemoglobin approaches a level where transfusions may be required.

• Discontinue:

  • Therapy should be stopped after completion of chemotherapy or if after 8 weeks of therapy there is no hemoglobin response or RBC transfusions still required.

Darbepoetin alfa (Aranesp) dose in the treatment of symptomatic anemia in myelodysplastic syndromes (off-label):

• SubQ: 150 to 300 mcg once weekly or 500 mcg once every 2 to 3 weeks.

Conversion from epoetin alfa to darbepoetin alfa in CKD (on dialysis): See table

Conversion From Epoetin Alfa to Darbepoetin Alfa in Chronic Kidney Disease (Estimated Initial Dose)

Previous Dosage of Epoetin Alfa (units/week)	Darbepoetin Alfa Dosage (mcg/week)
<1,500	6.25
1,500 to 2,499	6.25
2,500 to 4,999	12.5
5,000 to 10,999	25
11,000 to 17,999	40
18,000 to 33,999	60
34,000 to 89,999	100
≥90,000	200
Note: Darbepoetin is given once weekly in patients receiving epoetin alfa 2 to 3 times per week. In patients receiving epoetin alfa once weekly, darbepoetin alfa is administered once every 2 weeks. The darbepoetin alfa dose to be administered every 2 weeks is derived by adding together 2 weekly epoetin alfa doses and then converting to the appropriate darbepoetin alfa dose. Dose titration depends on hemoglobin response thereafter. The dose conversion in this table does not accurately estimate the once-monthly dose in chronic kidney disease (CKD) patients, not on dialysis.

Darbepoetin alfa (Aranesp) dose in children:

Note:

• Close monitoring and individualized dosing are recommended.
• Use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

Darbepoetin alfa (Aranesp) dose in the treatment of anemia associated with chronic kidney disease (ON dialysis):

Note:

• IV route is preferred for hemodialysis patients.
• Treatment should be started when hemoglobin is <10 g/dl.
• Dose reduction or interruption is required if hemoglobin approaches or exceeds 12 g/dl(if <18 years of age) or 11 g/dl (if ≥18 years of age).

• Initial: IV (preferred), SubQ:

  • Infants, Children, and Adolescents <18 years:
    • 0.45 mcg/kg once weekly.
  • Adolescents ≥18 years:
    • 0.45 mcg/kg once weekly or
    • 0.75 mcg/kg once every 2 weeks.

Dosage adjustment:

• Infants, Children, and Adolescents:
• IV (preferred), SubQ:
  • The dose should not be increased more frequently than every 4 weeks (dose decreases may occur more frequently).
  • Dose reduction by 25% should be done if hemoglobin increases >1 g/dL in any 2-week period.
  • If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%
  • Inadequate or lack of response:
    • If adequate response is not achieved over 12 weeks, further increases are unlikely to be of benefit and may increase the risk for adverse events, the lowest effective dose should be given to maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate the patient for other causes of anemia.
    • Therapy should be stopped if responsiveness does not improve.

Darbepoetin alfa (Aranesp) dose in the treatment of anemia associated with chronic kidney disease (NO dialysis): Note:

• Treatment should be started when hemoglobin is <10 g/dL;
• use only if the rate of hemoglobin decline would likely result in RBC transfusion and desire is to reduce risk of alloimmunization or other RBC transfusion-related risks.
• Dose reduction or interruption is needed  if hemoglobin exceeds 12 g/dl (if age <18 years) or 10 g/dl (if age ≥18 years):

• Initial: IV, SubQ:

  • Infants, Children, and Adolescents <18 years:
    • 0.45 mcg/kg once weekly or 0.75 mcg/kg once every 2 weeks.
  • Adolescents ≥18 years:
    • 0.45 mcg/kg once every 4 weeks.

Dosage adjustment:

• Infants, Children, and Adolescents:
  • IV, SubQ: Dose should not be increased more frequently than every 4 weeks (dose decreases may occur more frequently).
  • Dose reduction by 25% should be done if hemoglobin increases >1 g/dL in any 2-week period.
  • If hemoglobin does not increase by >1 g/dl after 4 weeks: Increase dose by 25%
  • Inadequate or lack of response:
    • If adequate response is not achieved over 12 weeks, further increases are unlikely to be of benefit and may increase the risk for adverse events, the lowest effective dose should be used to maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate the patient for other causes of anemia.
    • Therapy should be stopped if responsiveness does not improve.

Conversion from epoetin alfa to darbepoetin alfa:

• Infants, Children, and Adolescents:

  • Determination of weekly darbepoetin dose is based on the weekly epoetin dose at the time of conversion; see the following table.

Conversion From Epoetin Alfa to Darbepoetin Alfa (IV or SubQ) (maintain the same route of administration for the conversion)

Previous Weekly Epoetin Alfa Dose (units/week)	Weekly Darbepoetin Alfa Dosage
	Age 1 month to <18 years (mcg/week)	Age ≥ 18 years (mcg/week)
<1,500	Not established	6.25
1,500 to 2,499	6.25	6.25
2,500 to 4,999	10	12.5
5,000 to 10,999	20	25
11,000 to 17,999	40	40
18,000 to 33,999	60	60
34,000 to 89,999 100	100	100
≥90,000	200	200
Note: Due to the longer serum half-life of darbepoetin alfa, when converting from epoetin alfa, administer darbepoetin alfa once weekly if the patient was receiving epoetin alfa 2 to 3 times weekly and administer darbepoetin alfa once every 2 weeks if the patient was receiving epoetin alfa once weekly.

Darbepoetin alfa (Aranesp) Pregnancy Risk Category: C

• Case reports have described the use of darbepoetinalfa during pregnancy.

Use of Darbepoetin Alfa during breastfeeding

• It is unknown if Darbepoetin alfa secretion occurs in breast milk
• The risk of infant exposure and the benefits of breastfeeding to the baby during therapy will all play a role in deciding whether to breastfeed.

Darbepoetin alfa (Aranesp) Dose adjustment in renal disease:

No dosage adjustment is necessary.

Darbepoetin alfa (Aranesp) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling.

---

Adverse reactions occurred in adults with chronic kidney disease unless otherwise specified.

Common Side Effects of Darbepoetin alfa (Aranesp):

• Cardiovascular:

  • Hypertension
  • Edema

• Gastrointestinal:

  • Abdominal pain

• Respiratory:

  • Dyspnea
  • Cough

Rare Side Effects of Darbepoetin alfa (Aranesp):

• Cardiovascular:

  • Procedural hypotension
  • Angina pectoris
  • Thrombosis
  • Thrombosis of vascular graft
  • Thromboembolism
  • Pulmonary embolism
  • Arterial thromboembolism

• Dermatologic:

  • Erythema of skin
  • Skin rash

• Endocrine & metabolic:

  • Hypervolemia

• Immunologic:

  • Antibody development

Side effects of Darbepoetin alfa (Aranesp) - Frequency not defined:

• Cardiovascular:

  • Myocardial infarction
  • Significant cardiovascular event

• Central nervous system:

  • Cerebrovascular disease

• Local:

  • Pain at injection site

Contraindications to Darbepoetin alfa (Aranesp):

• Severe allergic reaction to darbepoetinalfa or any other component of the formulation
• Hypertension uncontrolled
• Pure red cell aplasia (PRCA), which develops after treatment with darbepoetinalfa or other erythropoietin proteins drugs

Canadian labeling: Additional contraindications not in the US labeling

• Sensitivity to mammalian cell derived products

Warnings and precautions

• Cardiovascular events: [US Boxed Warn]

  • When administered to hemoglobin levels >11g/dL, erythropoietin stimulants increase the risk of stroke, serious myocardial injury, stroke, VTE, vascular accessibility thrombosis and death.
  • They also provide no additional benefit.
  • There is an increased risk if hemoglobin levels rise rapidly (>1 g/dl in less than 2 weeks).

• Cutaneous reactions:

  • These agents are known for causing allergic reactions such as Stevens-Johnson syndrome and erythema multiforme.
  • If there is a severe reaction to the therapy, it should be stopped.

• Hypersensitivity

  • Hypersensitivity reactions can include anaphylactic reactions, angioedema and bronchospasm.
  • In patients with serious allergic/anaphylactic reactions, therapy should be stopped immediately.

• Pure red cell aplasia

  • SubQ darbepoetin Alfa is used to treat chronic kidney disease. Patients with hemodialysis or hepatitis B can see anemia.
  • When darbepoetin suddenly stops working, it is necessary to evaluate for pure red cell aplasia and associated neutralizing antibodies.
  • Therapy should be stopped for patients suffering from pure red cell aplasia secondary or neutralizing antibodies to Erythropoietin.
  • Cross-reactivity can occur between antibodies, so switching to an ESA is not advised for patients with antibody-mediated anemia.

• Patients with cancer: [US Boxed Warn]

  • Patients with non-small cell lung cancer, such as breast, cervical, head, neck, lymphoid and lymphoid, have a shorter overall survival rate or higher risk of tumor progression.
  • Patients who receive ESAs with a target hemoglobin >=12 g/dL are at greater risk
  • [US Boxed Warnings]To reduce these risks and to lower the risk of cardiovascular and thrombovascular complications, it is important to give the lowest dose possible.
  • These agents should not be used to treat anemia caused by concurrent myelosuppressive chemotherapy. They should be stopped after the course of chemotherapy.
  • ESA is not recommended for patients receiving myelosuppressive treatment if the expected outcome is curative.
  • Dose modification is required if hemoglobin levels increase by more than 1 g/dL over a 2-week period.
  • Patients with anemia who had received chemotherapy for non-small-cell lung malignancy were randomized to receive darbepoetin. The results showed that darbepoetin was not superior to placebo in terms of overall survival and progression-free survival. However, darbepoetin did result in more thrombovascular events than the placebo arm.
  • Patients >65 years old with cancer are at greater risk for venous embolism if ESA is not given without reducing transfusions.
  • In controlled clinical trials, anemia symptoms, quality, fatigue, and well-being were not shown to be improved.

• Patients with chronic kidney disease: [US Boxed Warn]

  • Chronic kidney disease patients who have ESAs that target hemoglobin levels above 11 g/dl are at greater risk for stroke and fatal cardiovascular events.
  • To minimize the need to transfuse RBCs, it is important to use the lowest dose possible.
  • A hemoglobin level above 1 g/dl within 2 weeks is a sign of increased risk. Dosage reduction is recommended.
  • Dialysis's effectiveness is decreased due to an increase of red blood cells and decrease in plasma volume. Adjustments in dialysis parameters might be necessary.
  • Patients with chronic kidney disease who don't require dialysis have a better response to darbepoetin beta in lower doses.
  • Patients receiving darbepoetin must have a higher level of heparinization to prevent extracorporeal circuit clotting.

• Hypertension:

  • Patients with uncontrolled hypertension should not use it.
  • Hypertension can be exacerbated by an increase in hemoglobin.
  • The dose of darbepoetin should not be increased if hemoglobin levels exceed 1 g/dl within a 2-week period.
  • Before treatment, it is important to monitor your BP and keep it under control.
  • Hypertensive encephalopathy is a condition that can be caused by erythropoietin therapy.

• Patients undergoing perioperative surgery:

  • Patients who had coronary bypass surgery with epoetin experienced an increase in mortality due to thrombotic events.
  • Patients who have had surgery with epoetin are at greater risk for developing DVT.
  • Darbepoetin Alfa is not approved to reduce allogeneic red cell transfusions for patients who are scheduled for surgery.

• Seizures:

  • Darbepoetin can increase the risk of seizures in patients suffering from chronic kidney disease. Patients with seizures should not use darbepoetin.
  • During the first few months of therapy, neurologic symptoms should be closely monitored.

• Acute anemia or severe anemia:

  • Darbepoetin Alfa is not recommended as an emergency transfusion substitute or for acute correction for severe anemia.

Darbepoetin alfa: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Lenalidomide	Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Lenalidomide.
Nandrolone	May enhance the stimulatory effect of Erythropoiesis-Stimulating Agents. Specifically, nandrolone may enhance the erythropoiesis stimulatory effect of ErythropoiesisStimulating Agents.
Pomalidomide	Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Pomalidomide.
Thalidomide	Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Thalidomide.

 

Monitoring parameters:

• BP
• Hemoglobin (at least once per week until maintenance dose established and after dosage changes, monitor less frequently once hemoglobin is stabilized); CKD patients should be also be monitored at least monthly following hemoglobin stability)
• Iron stores (transferrin saturation and ferritin) before and during therapy
• Serum chemistry (CKD patients)
• fluid balance (CKD patients)
• Signs of seizures (CKD patients following initiation for the first few months, includes new-onset or change in seizure frequency or premonitory symptoms)
• Cancer patients: Examinations recommended by the ASCO/ASH guidelines
• Before therapy;
• Retics count
• peripheral blood smear (in some situations a bone marrow exam may be necessary),
• Iron, folate, or vitamin B deficiency
• RFTs
• Occult blood loss
• During ESA treatment, assess baseline and periodic iron, total iron-binding capacity, and transferrin saturation or ferritin levels.

How to administer Darbepoetin alfa (Aranesp)?

IV, SubQ:

• It can be given by SubQ or IV injection.
• The IV route is recommended in hemodialysis patients.
• Vigorous shaking may denature darbepoetin alfa, rendering it biologically inactive, therefore shaking should be avoided.
• It should not be diluted given in combination with other drug solutions.
• Any unused portion of the vial should be discarded, do not pool unused portions.

Mechanism of action of Darbepoetin alfa (Aranesp):

• Darbepoetin Alfa stimulates the division and differentiation committed erythroid progenitor cell cells, thereby inducing Erythropoiesis.
• It causes the release of reticulocytes (bone marrow cells) into the bloodstream.
• They mature to erythrocytes. This effect has a dose-response relationship. The reticulocyte number is therefore increased, which leads to an increase in hemoglobin and hematocrit.
• If Darbepoetin Alfa is administered S/Q or IV, its half-life can be as high as 3 times that of epoetin concentrations.

The onset of action:

• Increased hemoglobin levels not generally observed until 2 to 6 weeks after initiating treatment

Absorption: SubQ:

• Slow

Bioavailability: CKD: SubQ:

• Adults: ~37% (range: 30% to 50%)
• Children: 54% (range: 32% to 70%)

Half-life elimination: Note:

• Darbepoetin alfa half-life is approximately 3-fold longer than epoetin alfa following IV administration.

CKD:

• Children and Adolescents:
  • IV: Terminal: 22.1 ± 4.8 hours
  • SubQ: Terminal: 42.8 ± 23 hours
• Adults:
  • IV: 21 hours
  • SubQ:
    • Nondialysis patients:
      • 70 hours (range: 35 to 139 hours),
    • Dialysis patients:
      • 46 hours (range: 12 to 89 hours)

Cancer:

• Children and Adolescents: SubQ: 49.4 ± 32 hours
• Adults: SubQ: 74 hours (range: 24 to 144 hours)

Time to peak: SubQ: CKD:

• Children and Adolescents: 36.2 ± 14.1 hours
• Adults: 48 hours (range: 12 to 72 hours; independent of dialysis)

Cancer:

• Children and Adolescents: 87.5 ± 53 hours
• Adults: 71 hours (range: 28 to 120 hours)

International Brands of Darbepoetin alfa:

• Aranesp (Albumin Free)
• Aranesp (HSA-Free)
• Actorise
• Aranesp
• NESP
• Nespo

Darbepoetin alfa Brand Names in Pakistan:

No Brands Available in Pakistan.