REPOITIN 2000 2000 IU/0.5ML (1 DOSE) SOLUTION FOR INJECTION

Indications

• Anemia associated with chronic renal failure
• Anemia in patients undergoing chemotherapy

Mechanism of action

Erythropoietin binds to the erythropoietin receptor (EPO-R) on erythroid progenitor cells, activating intracellular signaling pathways, particularly the JAK2/STAT5 pathway. This binding induces a conformational change in EPO-R, activating JAK2 through phosphorylation. Activated JAK2 then phosphorylates tyrosine residues in the EPO-R cytoplasmic domain, serving as docking sites for signaling proteins, including phosphorylated STAT5. Once activated, STAT5 translocates to the nucleus, functioning as a transcription factor to stimulate genes that promote cell division and inhibit apoptosis, critical for erythroid differentiation.

Pharmacodynamics

Erythropoietin regulates erythrocyte differentiation and maintains physiological levels of circulating erythrocyte mass. It increases the reticulocyte count within 10 days of administration, followed by increases in RBC count, hemoglobin, and hematocrit within 2 to 6 weeks. In patients undergoing hemodialysis, doses exceeding 300 Units/kg three times weekly do not yield a greater biological response. Erythropoietin effectively stimulates erythropoiesis in patients with chronic renal failure and has also demonstrated efficacy in anemic patients receiving zidovudine for HIV and those undergoing chemotherapy.

Pharmacokinetics

Erythropoietin is administered via subcutaneous or intravenous routes. It has a half-life of approximately 4 to 13 hours, depending on the route of administration and the patient's condition. The onset of action is typically within days, with peak effects seen in 2 to 6 weeks. Renal function significantly affects its clearance, necessitating dosage adjustments in patients with renal impairment.

Contra-indications

• Uncontrolled hypertension
• Pure red cell aplasia following erythropoietin therapy
• Hypersensitivity to the active substance or any of the excipients

Adverse effects

• Hypertension
• Thrombotic events (e.g., stroke, myocardial infarction)
• Headache
• Fatigue
• Nausea
• Injection site reactions
• Seizures
• Allergic reactions

Interactions

• Antineoplastic agents may have an additive effect on blood pressure
• Iron supplements should be monitored as erythropoietin increases erythropoiesis and may require increased iron availability

Precautions

• Monitor blood pressure regularly during treatment
• Assess iron status before and during therapy
• Use with caution in patients with a history of seizures
• Caution in patients with a history of thromboembolic events

Pregnancy

Erythropoietin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data are available.

Breast-feeding

Erythropoietin is excreted in human milk; caution should be exercised when administered to nursing women.

Storage

Store in a refrigerator (2°C to 8°C). Do not freeze. Protect from light.

Formulations

• Injection solution in vials or pre-filled syringes containing epoetin alfa

Mechanism of action

Erythropoietin 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. Epoetin alfa is a glycoprotein, produced by recombinant DNA technology, that contains 165 amino acids in a sequence identical to that of endogenous human erythropoietin. Recombinant epoetin has the same biological activity as the endogenous hormone, which induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells, including burst-forming units-erythroid, colony-forming units- erythroid, erythroblasts, and reticulocytes, in bone marrow. Erythropoietin also induces the release of reticulocytes from the bone marrow into the blood stream, where they mature into erythrocytes. Endogenous erythropoietin is produced primarily in the kidney. The anemia associated with chronic renal failure is caused primarily by inadequate production of the hormone. Administration of epoetin corrects the erythropoietin deficiency in patients with chronic renal failure. Epoetin also stimulates red blood cell production in patients who do not have a documented erythropoietin deficiency, i.e., patients with normal or slightly elevated concentrations of endogenous erythropoietin. However, it may not be effective in patients who are anemic despite having significantly elevated concentrations of erythropoietin.

Pharmacodynamics

Erythropoietin and epoetin alfa are involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. It is reported to increase the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Depending on the dose administered, the rate of hemoglobin increase may vary. In patients receiving hemodialysis, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly. Epoetin alfa serves to restore erythropoietin deficiency in pathological and other clinical conditions where normal production of erythropoietin is impaired or compromised. In anemic patients with chronic renal failure (CRF), administration with epoetin alfa stimulated erythropoiesis by increasing the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Epoetin alfa was shown to be effective in increasing hematocrit in zidovudine-treated HIV-infected patients and anemic cancer patients undergoing chemotherapy.