Singapore Drugs Database

Indication

Indicated in adult and paediatric patients for the: - treatment of anemia due to Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis. - treatment of anemia due to zidovudine in patients with HIV-infection. - treatment of anemia due to the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. - reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery.

Mechanism of Action

Erythropoietin or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways [A33079]. The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM [A33080]. Upon binding to EPO-R on the surface of erythroid progenitor cells, a conformational change is induced which brings EPO-R-associated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity. JAK2 molecules are subsequently activated via phosphorylation, then phosphorylate tyrosine residues in the cytoplasmic domain of the EPO-R that serve as docking sites for Src homology 2-domain-containing intracellular signaling proteins [A33079]. The signalling proteins include STAT5 that once phosphorylated by JAK2, dissociates from the EPO-R, dimerizes, and translocates to the nucleus where they serve as transcription factors to activate target genes involved in cell division or differentiation, including the apoptosis inhibitor Bcl-x [A33079]. The inhibition of apoptosis by the EPO-activated JAK2/STAT5/Bcl-x pathway is critical in erythroid differentiation. Via JAK2-mediated tyrosine phosphorylation, erythropoietin and epoetin alfa also activates other intracellular proteins involved in erythroid cell proliferation and survival, such as Shc , phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1 [A33079].

Pharmacokinetics

Absorption

The time to reach peak concentration is slower via the subcutaneous route than the intravenous route which ranges from 20 to 25 hours, and the peak is always well below the peak achieved using the intravenous route (5–10% of those seen with IV administration) [A33080, L85]. The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40% [A33080, L85]. **Adult and paediatric patients with CRF:** Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours [FDA Label]. **Cancer patients receiving cyclic chemotherapy:** The average time to reach peak plasma concentration was approximately 13.3 ± 12.4 hours after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The Cmax is expected be 3- to 7- fold higher and the Tmax is expected to be 2- to 3-fold longer in patients receiving a 40,000 Units SC weekly dosing regimen [FDA Label].

Distribution

In healthy volunteers, the volume of distribution of intravenous epoetin alfa was generally similar to the plasma volume (range of 40–63.80 mL/kg), indicating limited extravascular distribution [A33080, A33076].

Metabolism

Binding of erythropoietin and epoetin alfa to EPO-R leads to cellular internalization, which involves the degradation of the ligand. Erythropoietin and epoetin alfa may also be degraded by the reticuloendothelial scavenging pathway or lymphatic system [A33080].

Elimination

Clearance

**Healthy volunteers: ** In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg [A33076]. **Cancer patients receiving cyclic chemotherapy:** The average clearance was approximately 20.2 ± 15.9 mL/h/kg after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing [FDA Label]. The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg) [FDA Label].

Toxicity

Overdose from epoetin alfa include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including cardiovascular events. Patients with suspected or known overdose should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the overdose, reintroduction of epoetin alfa therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the dose in accordance with the recommendations described in the drug label [FDA Label].

Active Ingredient/Synonyms

E.P.O. | Epoetin alfa | Epoetin alfa rDNA | Epoetin alfa-epbx | Epoetin alfa, recombinant | Epoetin beta | Epoetin beta rDNA | Epoetin epsilon | Epoetin gamma | Epoetin gamma rDNA | Epoetin kappa | Epoetin omega | Epoetin theta | Epoetin zeta | Epoetina dseta | Epoétine zêta | Epoetinum zeta | Erythropoiesis stimulating factor | Erythropoietin (human, recombinant) | Erythropoietin (recombinant human) | ESF | SH-polypeptide-72 | Erythropoietin |