ERYTHROPOIESIS- STIMULATING AGENTS

Patients who are no longer able to produce enough erythropoietin in the kidneys may benefit from treatment with exogenous erythropoietin, which is available as the drugs epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). When agents are used to stimulate the bone marrow to make more RBCs, it is important to ensure that the patient has adequate levels of the components required to make RBCs, including adequate iron.

Therapeutic Actions and Indications Epoetin alfa acts like the natural glycoprotein erythropoietin to stimulate the production of RBCs in the bone marrow (Figure 49.2). This drug is indicated in the treatment of anemia associated with renal failure and for patients on dialysis; for anemia associated with AIDS therapy; and for anemia associated with cancer chemotherapy when the bone marrow is depressed and the kidneys may be affected by the toxic drugs (Procrit only).

Pharmacokinetics All of these drugs can be given IV or by subcutaneous injection. Epoetin alfa, which is like endogenous erythropoietin,is metabolized in the serum through the normal process that the body uses to clear erythropoietin. It has a slow onset and peaks in 5 to 24 hours, and its duration of effect is usually 24 hours. It has a half-life of 4 to 13 hours and is excreted in the urine. Darbepoetin alfa has a half-life of 21 hours after intravenous (IV) administration or 49 hours after subcutaneous administration.

It reaches peak effects in 14 hours (if given IV) or 34 hours (subcutaneously). Duration of effects is 24 to 72 hours, and excretion is through the urine. Peginesatide has a half-life of hours. It has a slow onset and reaches peak effects in 48 hours. It is also cleared in the serum and excreted in the urine. It is not known whether epoetin alfa or peginesatide enters breast milk.

Contraindications and Cautions All three of these drugs are contraindicated in the presence of uncontrolled hypertension because of the risk of even further hypertension when RBC numbers increase and the pressure within the vascular system increases;with known hypersensitivity to any component of the drug to avoid hypersensitivity reactions; and with lactation because of the potential for allergic-type reactions with the neonate. There are no adequate studies in pregnancy,and so use should be limited to those situations in which the benefi t to the mother clearly outweighs the potential risk to the fetus.

Use caution when administering any of these drugs to patients with normal renal functioning and adequate levels of erythropoietin because of the rebound decrease in erythropoietin that will occur and when administering them to a patient with anemia and normal renal function because this can cause more severe anemia.

Adverse Effects The adverse effects most commonly associated with these drugs include the CNS effects of headache, fatigue, asthenia,and dizziness and the potential for serious seizures. These effects may be the result of a cellular response to the glycoprotein. Nausea, vomiting, and diarrhea also are common effects. Cardiovascular symptoms can include hypertension, edema, and possible chest pain, all of which may be related to the increase in RBC numbers changing the balance within the cardiovascular system.

Serious cardiovascular effects and increased risk of DVTs have been seen when the hemoglobin becomes higher than 12 g/dL. Patients receiving IV administration must also be monitored for possible clotting of the access line related to direct cellular effects of the drug. Rapid growth of cancer is seen when hemoglobin becomes higher than 12 g/dL. Postmarketing studies showed that pure red cell aplasia associated with erythropoietin-neutralizing antibodies could occur with all of these products. In 2008,after analyses of several postmarketing studies, these drugs were required to add black-box warnings to their prescribing information as reported in the Focus on Safe Medication Administration below.