ARANESP® (darbepoetin alfa) injection

ARANESP® (darbepoetin alfa) injection

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ARANESP® (darbepoetin alfa) injection

Darbepoetin alfa is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Darbepoetin alfa is a 165-amino acid protein that differs from recombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons.

Aranesp (darbepoetin alfa) injection is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 ± 0.2).

Indications and usage

  • 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

Mechanism of Action

Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.

Dosage and administration

Recommended starting dose for patients with CKD on dialysis:

  • 0.45 mcg/kg intravenously or subcutaneously weekly, or
  • 0.75 mcg/kg intravenously or subcutaneously every 2 weeks – Intravenous route is recommended for patients on hemodialysis

Recommended starting dose for patients with CKD not on dialysis:

  • 0.45 mcg/kg intravenously or subcutaneously at 4 week intervals

Recommended starting dose for pediatric patients with CKD:

  • 0.45 mcg/kg intravenously or subcutaneously weekly
  • patients with CKD not on dialysis may also be initiated at 0.75 mcg/kg every 2 weeks

Recommended starting dose for patients with cancer on chemotherapy (2.3):

  • 2.25 mcg/kg subcutaneously weekly, or
  • 500 mcg subcutaneously every 3 weeks

Contraindications

  • Uncontrolled hypertension
  • Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs
  • Serious allergic reactions to Aranesp

Adverse reactions

Patients with CKD: Adverse reactions in ≥ 10% of Aranesp-treated patients in clinical studies were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension

Patients with Cancer Receiving Chemotherapy: Adverse reactions in ≥ 1% of Aranesp-treated patients in clinical studies were abdominal pain, edema, and thrombovascular events

Warnings and precautions

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

  • In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 – 11.3 g/dL), Aranesp and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
  • Using Aranesp to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke
  • In controlled clinical trials of patients with cancer, Aranesp and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
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  • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures

Hypertension: Aranesp is contraindicated in patients with uncontrolled hypertension. In Aranesp clinical studies, approximately 40% of patients with CKD required initiation or intensification of antihypertensive therapy during the early phase of treatment. Hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Aranesp.

Seizures: Aranesp increases the risk of seizures in patients with CKD. During the first several months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

Lack or Loss of Hemoglobin Response to Aranesp: For lack or loss of hemoglobin response to Aranesp, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA

Pure Red Cell Aplasia: Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp is not approved).

Serious Allergic Reactions: Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp. Immediately and permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

Severe Cutaneous Reactions: Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Aranesp) in the post-marketing setting. Discontinue Aranesp therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

Dialysis Management: Patients may require adjustments in their dialysis prescriptions after initiation of Aranesp. Patients receiving Aranesp may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Use in specific populations

Pregnancy: The limited available data on Aranesp use in pregnant women are insufficient to determine a drug-associated risk of major birth defects or miscarriage. In animal reproductive and developmental toxicity studies, Aranesp increased early post-implantation loss at doses approximating the clinical recommended starting doses. Consider the benefits and risks of Aranesp for the mother and possible risks to the fetus when prescribing Aranesp to a pregnant woman

Lactation: There is no information regarding the presence of Aranesp in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Aranesp and any potential adverse effects on the breastfed child from Aranesp or from the underlying maternal condition.

Pediatric Use:

  • Pediatric Patients with CKD: The safety and effectiveness of Aranesp in pediatric patients with CKD receiving and not receiving dialysis have been established in the age groups 1 month to 16 years old.
  • Pediatric Patients with Cancer: The safety and efficacy of Aranesp in pediatric patients with cancer have not been established.

Overdosage

Aranesp overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Aranesp dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs

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