Pharmacotherapeutic Group: Other antianaemic preparations. ATC Code: B03XA01.
Pharmacology: Pharmacodynamics: Erythropoietin is a glycoprotein that stimulates, as a mitosis-stimulating factor and differentiating hormone, the formation of erythrocytes from precursors of the stem cell compartment.
The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton. The protein fraction of the molecule contributes about 58% and consists of 165 amino acids. The four carbohydrate chains are attached via three N-glycosidic bonds and one O-glycosidic bond to the protein. Epoetin alfa obtained by gene technology is glycosylated and is identical in its amino acid and carbohydrate composition to endogenous human erythropoietin that has been isolated from the urine of anaemic patients.
Epoetin alfa has the highest possible purity according to the present state of the art. In particular, no residues of the cell line used for the production are detectable at the concentrations of the active ingredient that are used in humans.
The biological efficacy of epoetin alfa has been demonstrated in various animal models in vivo (normal and anaemic rats, polycythaemic mice). After administration of epoetin alfa, the number of erythrocytes, the Hb values and reticulocyte counts increase as well as the 59Fe-incorporation rate.
An increased 3H-thymidine incorporation in the erythroid nucleated spleen cells has been found in vitro (mouse spleen cell culture) after incubation with epoetin alfa.
It could be shown with the aid of cell cultures of human bone marrow cells that epoetin alfa stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin alfa on bone marrow cells could not be detected.
721 cancer patients receiving non-platinum chemotherapy were included in three placebo-controlled studies, 389 patients with haematological malignancies (221 multiple myeloma, 144 non-Hodgkin's lymphoma and 24 other haematological malignancies) and 332 with solid tumours (172 breast, 64 gynaecological, 23 lung, 22 prostate, 21 gastrointestinal, and 30 other tumour types). In two large, open-label studies, 2697 cancer patients receiving non-platinum chemotherapy were included, 1895 with solid tumours (683 breast, 260 lung, 174 gynaecological, 300 gastrointestinal, and 478 other tumour types) and 802 with haematological malignancies.
In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anaemic patients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of anaemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy-Anaemia (FACT-An) general scale, FACT-An fatigue scale and Cancer Linear Analogue Scale (CLAS). Two other smaller, randomised, placebo-controlled trials failed to show a significant improvement in quality of life parameters on the EORTC-QLQ-C30 scale or CLAS, respectively.
Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.
Survival and tumour progression have been examined in five large controlled studies involving a total of 2833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. The studies either recruited patients who were being treated with chemotherapy (two studies) or used patient populations in which ESAs are not indicated: anaemia in patients with cancer not receiving chemotherapy, and head and neck cancer patients receiving radiotherapy. The target haemoglobin concentration in two studies was >13 g/dl; in the remaining three studies it was 12-14 g/dl. In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anaemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group.
A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-, radio-, chemoradio-, or no therapy) participating in 53 controlled clinical trials involving several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95 % CI: 1.00, 1.12; 53 trials and 13,933 patients) and for the cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see Precautions).
Pharmacokinetics: Distribution: Intravenous route: Measurement of epoetin alfa following multiple dose intravenous administration revealed a half-life of approximately 4 hours in normal volunteers and a somewhat more prolonged half-life in renal failure patients, approximately 4-13 hours. A half-life of approximately 4-13 hours has been reported in children.
Subcutaneous route: Following subcutaneous injection, serum levels of epoetin alfa are much lower than the levels achieved following i.v. injection, the levels increase slowly and reach a peak between 5-24 hours. The peak is always well below the peak achieved using the i.v. route (approximately 1/20th of the value).
There is no accumulation: the levels remain the same, whether they are determined 24 hours after the first injection or 24 hours after the last injection.
The half-life is difficult to evaluate for the subcutaneous route and is estimated about 24 hours. The bioavailability of subcutaneous injectable epoetin alfa is much lower than that of the intravenous drug: approximately 20%.
Toxicology: Preclinical safety data: In some pre-clinical toxicological studies in dogs and rats, but not in monkeys, epoetin alfa therapy was associated with subclinical bone marrow fibrosis (bone marrow fibrosis is a known complication of chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of haemodialysis patients who were treated with epoetin alfa for 3 years compared to a matched control group of dialysis patients who had not been treated with epoetin alfa).
In animal studies, epoetin alfa has been shown to decrease foetal body weight, delay ossification and increase foetal mortality when given in weekly doses of approximately 20 times the recommended human weekly dose. These changes are interpreted as being secondary to decreased maternal body weight gain.
Epoetin alfa did not show any changes in bacterial and mammalian cell culture, mutagenicity tests and an in vivo micronucleus test in mice.
Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the literature regarding whether erythropoietins may play a role as tumour proliferators. These reports are based on in vitro findings from human tumour samples, but are of uncertain significance in the clinical situation.