Darbepoetin

Anemia may occur in patients with chronic renal failure as tlie result of the inability of the kidney to produce erythropoietin. Erythropoietin is a glycoprotein hormone synthesized mainly in the kidneys and used to stimulate and regulate the production of erythrocytes or red blood cells (RBCs). Failure to produce the needed erythrocytes results in anemia Two examples of drug used to treat anemia associated with chronic renal failure are epoetin alfa (Epogen) and darbepoetin alfa (Aranesp). 

Epoetin alfa (erythropoietin EPO) and darbepoetin alfa are usually well tolerated. The most common adverse reactions include hypertension, headache, tachycardia, nausea, vomiting, diarrhea, skin rashes, fever, myalgia, and skin reaction at tlie injection site. See the Summary Drug Table Drug Used in the Treatment of Anemia for more information on these drug. 

Epoetin alfa is contraindicated in patients with uncontrolled hypertension, those needing an emergency transfusion, or those with a hypersensitivity to human albumin. Darbepoetin alfa (Aranesp) is contraindicated in patients with uncontrolled hypertension or in those allergic to the drug. 

Epoetin alfa and darbepoetin alfa are used with caution in patients with hypertension, heart disease, congestive heart failure, or a history of seizures. Both of these drains are Pregnancy Category C dru and are used cautiously during pregnancy and lactation. 

Subcutaneous (SC) administration of ESA produces a more predictable and sustained response than IV administration, and is therefore the preferred route of administration for both agents. Intravenous administration is often utilized in patients who have established IV access or are receiving hemodialysis. Starting doses of ESAs depend on the patient s Hgb level, the target Hgb level, the rate of Hgb increase and clinical circumstances.31 The initial increase in Hgb should be 1-2 g/dL (0.6206-1.2404 mmol/L) per month. The starting doses of epoetin alfa previously recommended are 80 to 120 units/kg per week for SC administration and 120 to 180 units/kg per week for IV administration, divided two to three times per week. The starting dose of darbepoetin alfa is 0.45 mcg/kg administered SC or IV once weekly (Table 23-3). 

TABLE 23-3. Estimated Starting Doses of Darbepoetin Alfa Based on Previous Epoetin Alfa Dose... 

Previous Epoetin Alfa Dose (units/week) Weekly Darbepoetin Alfa Dose (mcg/week)... 

Subcutaneous versus intravenous erythropoietin or darbepoetin is usual, which may reduce overall doses and be more physiologic. 

Evaluate the proper use of epoetin and darbepoetin in anemia patients with cancer and kidney disease. 

Therapy with epoetin or darbepoetin can increase hemoglobin, decrease transfusion requirements, and improve quality of life in cancer and kidney disease patients with anemia. 

Studies have shown that in patients with chemotherapy-related anemia, therapy with erythropoietin products (epoetin-alfa and darbepoetin) can increase hemoglobin, decrease transfusion requirements, and improve quality of life.12 Epoetin is recombinant human erythropoietin, and darbepoetin is structurally similar to endogenous erythropoietin. Both bind to the same receptor to stimulate red blood cell production. Darbepoetin differs from epoetin in that it is a glycosylated form and exhibits a longer half-life in the body. The half-lives of a single subcutaneous injection of epoetin or darbepoetin in patients are roughly 27 and 43 hours, respectively. 

The National Comprehensive Cancer Network (NCCN) recommends an anemia work-up for patients with hemoglobin of less than 11 g/dL (110 g/L or 6.8 mmol/L). Patients who are symptomatic or asymptomatic with significant risk factors (e.g., extensive transfusion history, myelosuppressive chemotherapy, etc) may qualify for treatment with erythropoietic agents such as epoetin-alfa or darbepoetin. Data do not support the use of one agent over another they are both equally effective in treating this type of anemia.12 Table 63-4 provides dosing recommendations for chemotherapy-related anemia. 

Epoetin-alfa (Epogen, Procrit) Darbepoetin-alfa (Aranesp)... 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

Aranesp (darbepoetin alfa, a rEPO analogue) Anaemia associated with various medical conditions Amgen... 

Darbepoetin alfa has a longer half-life than epoetin alfa and prolonged biologic activity. Doses are administered less frequently, starting at once a week when administered IV or SC. 

Aranesp, Darbepoetin alfa Amgen, Inc. Anemia associated with chronic renal failure Chemotherapy-induced anemia in patients with non-myeloid malignancies Sept. 2001 July 2002... 

Administer IV or subcutaneously as a single weekly injection. Start and slowly adjust the dose as described below based on hemoglobin levels. If a patient fails to respond or maintain a response, consider other etiologies. When darbepoetin therapy is initiated or adjusted, follow the hemoglobin level weekly until stabilized, and monitor at least monthly thereafter. 

For patients who respond to darbepoetin with a rapid increase in hemoglobin (eg, more than 1 g/dL in any 2-week period), reduce the dose of darbepoetin. 

Correction of anemia The recommended starting dose of darbepoetin for the correction of anemia in chronic renal failure (CRF) patients is 0.45 mcg/kg body weight, administered as a single IV or subcutaneous injection once weekly. Titrate doses to not exceed a target hemoglobin concentration of 12 g/dL. Some patients have been treated successfully with subcutaneous darbepoetin administered once every 2 weeks. 

Conversion from epoetin alfa to darbepoetin Estimate the starting weekly dose of darbepoetin based on the weekly epoetin alfa dose at the time of substitution. Titrate doses to maintain the target hemoglobin. Due to the longer serum half-life, administer darbepoetin less frequently than epoetin alfa. Administer once a week if... 

If the increase in hemoglobin is less than 1 g/dL over 4 weeks and iron stores are adequate, the dose of darbepoetin may be increased by approximately 25% of the previous dose. Further increases may be made at 4-week intervals until the specified hemoglobin is obtained. 

Maintenance dose Adjust darbepoetin dosage to maintain a target hemoglobin not to exceed 12 g/dL. If the hemoglobin exceeds 12 g/dL, the dose may be adjusted as described above. 

Preparation Do not shake. Do not dilute. Do not administer darbepoetin in conjunction with other drug solutions. Darbepoetin is packaged in single-use vials and contains no preservatives. Discard any unused portion. Do not pool unused portions. 

Pharmacology Darbepoetin alfa is an erythropoiesis-stimulating protein produced by recombinant DNA technology. Darbepoetin stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. 

Absorption - Darbepoetin has an approximately 3-fold longer terminal half-life than epoetin alfa when administered by either the IV or subcutaneous route. Following IV administration, darbepoetin has a distribution half-life of approximately 1.4 hours and mean terminal half-life of approximately 21 hours. 

Distribution - The distribution of darbepoetin in adult CRF patients is predominantly confined to the vascular space (approximately 60 mL/kg). With once-weekly dosing, steady-state serum levels are achieved within 4 weeks with a less than 2-fold increase in peak concentration when compared with the initial dose. 

Hypertension Do not treat patients with uncontrolled hypertension with darbepoetin control blood pressure before initiation of therapy. Blood pressure may rise during treatment of anemia with darbepoetin or epoetin alfa. 

Seizures Seizures have occurred in patients with CRF participating in clinical trials of darbepoetin and epoetin alfa. During the first several months of therapy, closely monitor blood pressure and the presence of premonitory neurologic symptoms. Thrombotic events An increased incidence of thrombotic events has been observed in patients treated with erythropoietic agents. 

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