EPREX

What it is

EPREX is epoetin alfa (rch), a recombinant human erythropoietin. It is expressed in Chinese hamster ovary cells and has a 165 amino acid sequence identical to that of human urinary EPO. EPREX is supplied as a sterile preservative-free phosphate buffered protein solution in pre-filled syringes containing 1,000 IU, 2,000 IU, 3,000 IU, 4,000 IU, 5,000 IU, 6,000 IU, 8,000 IU, 10,000 IU, 20,000 IU, 30,000 IU or 40,000 IU in various volumes.

Approved indications

— Treatment of patients with symptomatic or transfusion requiring anaemia associated with chronic renal failure to improve quality of life by improving energy levels, exercise performance, fatigue and sleep patterns and by reducing the need for blood transfusions. — Treatment of anaemia in patients with non-myeloid malignancies where anaemia develops as a result of concomitantly administered chemotherapy, and where blood transfusion is not considered appropriate. — Treatment of adult patients with mild-to-moderate anaemia (haemoglobin > 100 to ≤ 130 g/L) scheduled for elective surgery with an expected moderate blood loss (2–4 units or 900 to 1800 mL) to reduce exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery. — Augmentation of autologous blood collection and limitation of the decline in haemoglobin in anaemic adult patients who are scheduled for major elective surgery and who are not expected to pre-deposit their complete peri-operative blood needs.

Dosing overview

During therapy, haematological parameters should be monitored regularly. Doses must be individualised to ensure that haemoglobin is maintained at an appropriate level for each patient. Dosing varies by indication. For adults scheduled for elective surgery, the recommended dose regimen is 600 IU/kg EPREX given weekly for three weeks (Days -21, -14, and -7) prior to surgery and on the day of surgery, administered subcutaneously. In cases where there is a medical need to shorten the lead time before surgery to less than three weeks, 300 IU/kg EPREX should be given daily for 10 consecutive days prior to surgery, on the day of surgery, and for four days immediately thereafter. For anaemic adult surgery patients in an autologous pre-donation programme, the recommended dose is 300–600 IU/kg twice weekly for three weeks, administered intravenously. For patients with chronic renal failure, the initial dosage in the correction phase is 50 IU/kg body weight three times a week intravenously or subcutaneously. If haemoglobin does not increase by 10 g/L after 1 month of treatment, the dosage may be raised to 75 IU/kg three times per week – and if further increments are needed they should be at 25 IU/kg, three times per week, at monthly intervals, to achieve a haemoglobin not to exceed 120 g/L. The recommended total weekly dose in the maintenance phase is between 75 and 300 IU/kg. For adult patients with cancer, the initial dose is 150 IU/kg given subcutaneously 3 times per week. If the haemoglobin has increased by at least 10 g/L or the reticulocyte count has increased ≥ 40,000 cells/microlitre above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg. If the haemoglobin increase is < 10 g/L and the reticulocyte count has increased < 40,000 cells/microlitre above baseline, increase the dose to 300 IU/kg.

Key safety warnings

An increased incidence of thrombotic vascular events has been observed in patients receiving EPREX. These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported. In all patients, haemoglobin concentrations should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin concentrations above the range for the indication of use. As with all growth factors, there is a concern that EPREX could stimulate the growth of tumours. In controlled clinical studies, use of EPREX and other ESAs have shown decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to a haemoglobin target of greater than 140 g/L, and shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to a haemoglobin target of 120-140 g/L. Blood pressure may rise during treatment of anaemia with EPREX. Hypertensive encephalopathy and seizures have been observed. Special care should be taken to closely monitor and control blood pressure in patients treated with EPREX. Antibody-mediated pure red cell aplasia (PRCA) (erythroblastopaenia) has been reported after treatment with erythropoietins. Most cases of PRCA associated with EPREX occurred in patients receiving subcutaneous administration.

Contraindications

EPREX is contraindicated in patients with uncontrolled hypertension, known sensitivity to mammalian cell derived products, or hypersensitivity to the active substance or to any of the excipients. EPREX is contraindicated in patients scheduled for elective surgery who are not participating in an autologous blood pre-deposit programme and who have severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident. EPREX is contraindicated in surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis or treatment. Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive EPREX or any other erythropoietin.

PBS listing

EPREX is listed on the PBS in multiple strengths: 1,000 units in 0.5 mL, 2,000 units in 0.5 mL, 3,000 units in 0.3 mL, 4,000 units in 0.4 mL, 5,000 units in 0.5 mL, 6,000 units in 0.6 mL, 8,000 units in 0.8 mL, 10,000 units in 1.0 mL, 20,000 units in 0.5 mL, and 40,000 units in 1.0 mL, all as pre-filled syringes. Each strength has 2 PBS items with streamlined restriction. Ex-manufacturer prices range from A$87.99 for the 1,000 unit strength to A$1,221.11 for the 20,000 unit strength.

Regulatory history

EPREX was first approved on 17 September 1998. The initial ARTG registration (1998-09-17) included five strengths: 1,000 IU/0.5 mL, 2,000 IU/0.5 mL, 3,000 IU/0.3 mL, 4,000 IU/0.4 mL, and 10,000 IU/1.0 mL injection syringes. Additional strengths were registered subsequently: 20,000 IU/0.5 mL and 40,000 IU/mL in 2000, and 5,000 IU/0.5 mL, 6,000 IU/0.6 mL, and 8,000 IU/0.8 mL in 2000, with the 30,000 IU/0.75 mL strength registered in 2008.