Therapeutic/Pharmacologic Class of Drug: Antianemic. ATC code: B03XA.
Pharmacology: The biological efficacy of epoetin beta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (normal and uremic rats, polycythemic mice, dogs). After administration of epoetin beta, 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 beta. Investigations in cell cultures of human bone marrow cells showed that epoetin beta stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin beta on bone marrow or on human skin cells were not detected.
After single dose administration of epoetin beta no effects on behavior or locomotor activity of mice and circulatory or respiratory function of dogs were observed.
Pharmacodynamics: Epoetin beta is identical in its amino acid and carbohydrate composition to erythropoietin that has been isolated from the urine of anemic patients. Erythropoietin is a glycoprotein that stimulates the formation of erythrocytes from its committed progenitors. It acts as a mitosis stimulating factor and differentiation hormone.
Mechanism of Action: Erythropoietin is a glycoprotein that, as a growth factor, primarily stimulates the formation of erythrocytes from its committed progenitors. It acts as mitosis stimulating factor and differentiation hormone.
Clinical/Efficacy Studies: This section describes recently completed randomized, controlled studies with epoetin beta in patients with renal anemia or cancer patients receiving chemotherapy/radiotherapy.
Patients with anemia due to chronic kidney disease: An open randomized study using epoetin beta was conducted in 605 pre-dialysis patients (CREATE) with mild to moderate anemia (Hb level: 11-12.5 g/dl). The primary objective was to explore whether high Hb correction (13-15 g/dl) would reduce cardiovascular (CV) morbidity as compared with standard anemia treatment (target Hb 10.5-11.5 g/dl). There was no benefit observed with high Hb correction compared to standard anemia correction. On the contrary, there were fewer events observed in the standard treatment group (47 versus 58 events, HR 0.78, p=0.20). A difference in time to initiation of dialysis was observed favoring the standard anemia correction group (111 and 127 events, median time to dialysis 41 months and 36 months, log rank test p=0.034, respectively), although no difference in median creatinine clearance over time between the two study groups was observed. Quality of life (assessed by SF-36 Health Survey Questionnaire) was significantly improved (p=0.003) in the high target Hb group at 1 year.
In another open randomized study in 172 patients with early diabetic nephrology, (ACORD) the effect of high Hb correction (target Hb 13-15 g/dl) and standard Hb correction (target Hb 10.5-11.5 g/dl) on cardiac structure and function was investigated.
At the end of the study, there was no significant difference between the two groups with respect to the primary parameter, the baseline adjusted left ventricular mass index (p=0.88). There was no statistically significant difference between the treatment groups in change from baseline in calculated creatinine clearance, time to doubling of serum creatinine, or an analysis of rapid progressors. The General Health score of the quality of life assessment (using the SF-36 Health Survey Questionnaire) was significantly improved (p=0.04) in the high target Hb group.
Cancer patients with symptomatic anemia receiving chemotherapy: In a placebo-controlled study using epoetin beta in 351 patients with head and neck cancer (ENHANCE), study drug was administered to maintain the hemoglobin levels of 14 g/dl in women and 15 g/dl in men. Locoregional progression free survival was significantly shorter in patients receiving epoetin beta (HR=1.62, p=0.0008). The results and interpretation of this study were confounded by imbalances between the treatment groups, especially with regard to tumor localization, smoking status and the heterogeneity of the study population.
A controlled, open-label, randomized study using epoetin beta in 463 patients with metastatic breast cancer receiving chemotherapy (BRAVE), which was designed to show a significant improvement in survival, did not show any statistically significant difference between the control and epoetin beta arms with regards to overall survival (p=0.52) or time to tumor progression (p=0.45). A greater number of patients in the control arm (64/232; 27.6%) had transfusion and severe anemic events compared with the epoetin beta arm (40/231; 17.3%) (p=0.009), reflecting the efficacy of epoetin beta treatment with respect to preventing transfusions by effective increase in hemoglobin.
A higher percentage of epoetin beta patients experienced thromboembolic events (TEEs) during the study compared with the control arm (13% versus 6%) and a shorter time to TEE for the epoetin beta treatment arm compared with control (p=0.008) was seen. However, the percentage of patients that experienced a serious TEE (3% control versus 4% epoetin beta) or TEE leading to death (2% in each arm) was comparable.
A controlled, open label, randomized study using epoetin beta in 74 patients with cervical cancer receiving radiochemotherapy (MARCH) did not show a correlation between hemoglobin increase and the reduction in treatment failures (response to radiochemotherapy). Therefore, it was decided not to proceed this study to its second stage.
A meta-analysis including all controlled clinical studies in anemic cancer patients treated with epoetin beta was performed (12 studies with a total of 2301 patients). The results from this present meta-analysis confirm the known efficacy of epoetin beta with respect to increases in hemoglobin levels and a reduced risk of blood transfusion.
In the overall population including also patients with Hb initiation levels up to 13 g/dl, no statistically significant increase in risk of death in the epoetin beta group compared with the control group (HR: 1.13, 95% CI 0.87 to 1.46, p=0.34) was observed. In patients with baseline hemoglobin ≤ 11 g/dl, the HR for overall survival was 1.09 (95 % CI 0.80 to 1.47, p=0.58). For time to disease progression the HR was 0.85 (95% CI: 0.72 to 1.01, p=0.07) in the overall patient population. When the analysis was restricted to patients with baseline hemoglobin ≤ 11 g/dl the HR was 0.80 (95% CI 0.65 to 0.99, p=0.04).
This meta analysis also confirmed the increased rate of thromboembolic events (TEE) reported (see Adverse Reactions) with a TEE rate of 7% in the epoetin beta group compared with 4% in the control group.
Immunogenicity: (see General under Precautions).
Pharmacokinetics: Pharmacokinetic investigations in healthy volunteers and uremic patients show that the half-life of intravenously administered epoetin beta is between 4 and 12 hours and that the distribution volume corresponds to one to two times the plasma volume. Analogous results have been found in animal experiments in uremic and normal rats.
Absorption: After subcutaneous administration of epoetin beta to uremic patients, the protracted absorption results in a serum concentration plateau, whereby the maximum concentration is reached after an average of 12 to 28 hours.
Bioavailability of epoetin beta after subcutaneous administration is between 23 and 42% as compared with intravenous administration.
Distribution: Pharmacokinetic investigations in healthy volunteers and uremic patients show that the distribution volume corresponds to one to two times the plasma volume.
Metabolism: Not applicable.
Elimination: Pharmacokinetic investigations in healthy volunteers and uremic patients show that the half-life of intravenously administered epoetin beta is between 4 and 12 hours.
After subcutaneous administration of epoetin beta to uremic patients, the terminal half-life is higher than after intravenous administration, with an average of 13 - 28 hours.
Pharmacokinetics in Special Populations: No formal study of the effect of hepatic impairment on the pharmacokinetics of epoetin beta was conducted.
Toxicology: Nonclinical Safety: Carcinogenicity: A carcinogenicity study with homologous erythropoietin in mice did not reveal any signs of proliferative or tumorigenic potential.
Genotoxicity: Not applicable.
Impairment of Fertility: Not applicable.
Reproductive Toxicity: Not applicable.
Other: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity of reproduction.