Pharmacotherapeutic Group: Anti-anaemic. ATC Code: B03XA01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the key regulator of red blood cell (RBC) production. EPO is involved in all phases of erythroid development, and has its principal effect at the level of erythroid precursors. After EPO binds to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosis and stimulates erythroid cell proliferation. Recombinant human EPO (Epoetin alfa), expressed in Chinese hamster ovary cells, has a 165 amino acid sequence identical to that of human urinary EPO; the 2 are indistinguishable on the basis of functional assays. The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton.
Pharmacodynamic responses to HSA-free Epoetin alfa, change in percent reticulocytes, haemoglobin, and total red blood cell counts as well as the area under the curve (AUCs) of these pharmacodynamic parameters, were similar between two dosing regimens (150 IU/kg SC three times per week to 40,000 IU/mL SC once weekly).
ESAs are growth factors that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.
Clinical Efficacy and Safety: Chronic Renal Failure: Epoetin alfa has been studied in clinical trials in adult anaemic CRF patients, including patients on dialysis and patients not yet on dialysis, to treat anaemia and maintain haematocrit within a concentration range of 30-36%.
In clinical trials at starting doses of 50-150 IU/kg three times per week, approximately 95% of all patients responded with a clinically significant increase in haematocrit. After approximately two months of therapy, virtually all patients were transfusion-independent. Once the haematocrit concentration range was achieved, the maintenance dose was individualised for each patient.
In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dose necessary to maintain the haematocrit between 30-36% was approximately 75 IU/kg given three times per week.
In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients on haemodialysis, clinically and statistically significant improvement was shown in the patients treated with Epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients from the group treated with Epoetin alfa were also enrolled in an open-label extension study which demonstrated improvements in their quality of life were maintained for an additional 12 months.
Adult Patients with Renal Insufficiency Not Yet Undergoing Dialysis: In clinical trials conducted in patients with CRF not on dialysis treated with Epoetin alfa, the average duration of therapy was nearly five months. These patients responded to Epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in haematocrit when Epoetin alfa was administered by either an intravenous or subcutaneous route. Similar rates of rise of haematocrit were noted when Epoetin alfa was administered by either route. Moreover, Epoetin alfa doses of 75-150 IU/kg per week have been shown to maintain haematocrits of 36-38% for up to six months.
In a study with extended interval maintenance dosing of EPREX (once weekly, once every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain adequate haemoglobin levels and reached protocol-defined haemoglobin withdrawal criteria (0% in once weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4 weeks groups).
A randomized prospective trial (CHOIR) evaluated 1432 anaemic chronic renal failure patients who were not undergoing dialysis. Patients were assigned to Epoetinum alfa treatment targeting a maintenance haemoglobin level of 13.5 g/dL (higher than the recommended target haemoglobin level) or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%) among the 717 patients in the lower haemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).
Treatment of Patients with Chemotherapy Induced Anaemia: Epoetinum alfa has been studied in clinical trials in adult anaemic cancer patients with lymphoid and solid tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these trials, Epoetin alfa administered three times a week (tiw) and once weekly has been shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in anaemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received Epoetin alfa and a maintenance of effect was observed.
Available evidence suggests the hematopoietic response to Epoetin alfa therapy is similar between patients with non-myeloid hematologic and solid tumors and in patients with or without tumor bone marrow infiltration. Comparable intensity of chemotherapy in the Epoetin alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area under the neutrophil time curve in patients treated with Epoetin alfa and placebo-treated patients, as well as by a similar proportion of patients in groups treated with Epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1000 and 500 cells/microL.
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).
The totality of evidence, including results of meta-analyses and clinical experience from controlled studies of ESAs in patients with cancer, continues to support a favorable benefit-risk balance for the use of ESAs in patients with chemotherapy-induced anemia, when used according to the prescribing information. In meta-analyses of studies in which patients were receiving chemotherapy there were no statistically significant increases in either mortality or tumour progression. Signals in individual studies conducted outside of the recommendations in the product labeling (hemoglobin targets above 12 g/dL and/or no chemotherapy treatment) have raised concerns (see Precautions).
Pharmacokinetics: Intravenous Administration: Measurement of Epoetin alfa following multiple dose intravenous (IV) administration of 50 to 100 IU/kg revealed a half-life of approximately 4 hours in healthy subjects and a longer half-life in renal failure patients of approximately 5 hours after doses of 50, 100 and 150 IU/kg. A half-life of approximately 6 hours has been reported in children. With at least 4 days of PK blood sampling, half-life estimates ranging from 20.1 to 33.0 hours were observed in cancer subjects receiving 667 and 1500 IU/kg IV doses of Epoetin alfa.
Subcutaneous Administration: Serum concentrations following subcutaneous injection are lower than those following intravenous injection. Serum levels increase slowly and reach a peak 12 to 18 hours after subcutaneous dosing. The peak serum concentration is below the peak observed using the intravenous route (approximately 1/20th of the value).
There is no accumulation: serum levels remain the same, whether data are collected 24 hours after the first injection or 24 hours after the last injection. Concentration-time profiles of erythropoietin on week 1 and week 4 were similar during multiple dosing of 600 IU/kg/once weekly in healthy subjects.
The pharmacokinetic data indicate no apparent difference in half-life among adult patients above or below 65 years of age.
A study of 7 preterm very low birth weight neonates and 10 healthy adults given IV erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
The half-life for the subcutaneous route of administration is approximately 24 hours. Mean half-life values in healthy subjects were 19.4 ± 8.1 and 15.0 ± 6.1 with multiple dosing of 150 IU/kg three times per week and 40,000 IU/mL once weekly, respectively.
In a study comparing 40,000 IU SC once weekly to 150 IU/kg SC three times per week dosing regimens of HSA-free Epoetin alfa in healthy subjects, the following parameters were estimated using data corrected for predose endogenous erythropoietin concentration during Week 4 (see Table 3.)
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Based on AUC comparison, relative bioavailability of Epoetin alfa 40,000 IU/mL once weekly versus 150 IU/kg three times per week was 239%.
The bioavailability of subcutaneous Epoetin alfa after a dose of 120 IU/kg is much lower than that of the intravenous drug: approximately 20%.
Pharmacokinetics of HSA-free Epoetin alfa were studied in anemic cancer subjects receiving cyclic chemotherapy after the 150 IU/kg three times per week and 40,000 IU/mL once weekly dosing regimens. In general, there was a high degree of variability associated with the pharmacokinetic parameters in anemic cancer subjects. In general, the first pharmacokinetic profile of Epoetin alfa during week 1 (when the anemic cancer subjects were receiving chemotherapy) demonstrated higher Cmax, increased half-life, and lower clearance than the second pharmacokinetic profile during Week 3 or 4 (when the anemic cancer subjects were not receiving chemotherapy) (see Table 4).
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Toxicology: Preclinical Safety Data: Chronic Toxicity: 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; it may be related to secondary hyperparathyroidism or unknown factors. In one study, there was no difference in the incidence of bone marrow fibrosis in haemodialysis patients treated with Epoetin alfa for 3 years and haemodialysis patients not treated with Epoetin alfa.
Carcinogenicity: Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the literature regarding ESAs as tumour proliferators. The clinical significance of these reports, based on in vitro findings from human tumour samples, are unknown.
Mutagenicity: Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.
Reproduction Toxicology: Preclinical studies have shown no evidence of teratogenicity in rats or rabbits at dosages up to 500 IU/kg/day administered intravenously. However, intravenous administration of Epoetin alfa causes a slight but not statistically significant decrease in fertility at 500 IU/kg, increased pre- and post-implantation loss and decreased fetal body weight at 100 and 500 IU/kg/day and delayed ossification at 20, 100, and 500 IU/kg/day. The latter finding was associated with reduced maternal body weight. Intravenous administration to lactating rats resulted in decreases in body weight gain, delays in appearance of abdominal hair and eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 IU/kg/day group. There were no Epoetin alfa-related effects on the F2 generation fetuses.