Erythropoiesis Stimulating Factor

Uses

Anaemia in zidovudine-treated HIV-infected patients, Anaemia of chronic renal failure, Anaemia of prematurity, Anaemia related to non-myeloid malignant disease chemotherapy, To reduce the need for allogenic blood tranfusion.

Erythropoiesis Stimulating Factor is also used to associated treatment for these conditions: Anemia, Anemia caused by Zidovudine, Reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery

How Erythropoiesis Stimulating Factor works

Erythropoiesis Stimulating Factor or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways . The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM . 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 . 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 . 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 .

Dosage

Erythropoiesis Stimulating Factor dosage

Increase yield of autologous blood As epoetin alfa or zeta: 600 IU/kg twice wkly for 3 wk before surgery.Anaemia of chronic renal failure As epoetin alfa:

• Predialysis and haemodialysis: Initial: 50 IU/kg 3 times/wk;
• Peritoneal dialysis: 50 IU/kg twice wkly.

Anaemia in zidovudine-treated HIV-infected patients As epoetin alfa: Initial: 100 IU/kg 3 times/wk for 8 wk. Max: 300 IU/kg 3 times/wk.

Anaemia related to non-myeloid malignant disease chemotherapy As epoetin alfa or zeta: Initial: 150 IU/kg 3 times/wk, up to 300 IU/kg 3 times/wk.

Anaemia of chronic renal failure:

• Child: As epoetin alfa: Initially, 50 IU/kg 3 times wkly. May increase dose at 4 wkly intervals in increments of 25 IU/kg 3 times wkly until a target haemoglobin concentration of 9.5-11 g/100 mL is reached. Usual maintenance dose: 30 kg: 90-300 IU/kg/wk.

Side Effects

Hypertension, myalgia, arthralgia, flu-like syndrome, rashes and urticaria. Potentially Fatal: Hypertensive crisis with encephalopathy-like symptoms e.g. headache, confusion, generalised seizures. Thrombosis.

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 .

Precaution

Chronic renal failure, ischaemic heart diseases, hypertension, pregnancy, seizures, liver dysfunction, lactation.

Interaction

Haematinics enhance efficiency. Increased dose of heparin in patients undergoing dialysis.

Food Interaction

• Administer iron supplement. When initiating an erythropoiesis-stimulating agent, evaluate iron stores and start iron supplementation if indicated. Most patients with chronic kidney disease require iron supplementation while taking an erythropoiesis-stimulating agent.

Volume of 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 .

Elimination Route

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) . The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40% .

Adult and paediatric patients with CRF: Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours .

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 .

Half Life

Healthy volunteers: The half life is approximately 4 hours in healthy volunteers receiving an intravenous injection . A half-life of approximately 6 hours has been reported in children .

Adult and paediatric patients with CRF: The elimination half life following intravenous administration ranges from 4 to 13 hours, which is about 20% longer in CRF patients than that in healthy subjects. The half life is reported to be similar between adult patients receiving or not receiving dialysis .

Cancer patients receiving cyclic chemotherapy: Following subcutaneous administration, the average half life is 40 hours with range of 16 to 67 hours .

Clearance

*Healthy volunteers: * In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg .

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 . The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg) .

Elimination Route

Erythropoiesis Stimulating Factor and epoetin alfa are cleared via uptake and degradation via the EPO-R-expressing cells, and may also involve other cellular pathways in the interstitium, probably via cells in the reticuloendothelial scavenging pathway or lymphatic system . Only a small amount of unchanged epoetin alfa is found in the urine .

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Uncontrolled hypertension, hypersensitivity to mammalian cell products and human albumin.

Storage Condition

Refrigerate at 2-8° C. Do not freeze.

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