EPREX® PRODUCT

About EPREX®

Erythropoietin is a glycoprotein which stimulates red blood cell production. It is produced in the kidney and stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. PROCRIT (Epoetin alfa), a 165 amino acid glycoprotein manufactured by recombinant DNA technology, has the same biological effects as endogenous erythropoietin. (1) It has a molecular weight of 30,400 daltons and is produced by mammalian cells into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural erythropoietin. PROCRIT is formulated as a sterile, colorless, liquid in an isotonic sodium chloride/sodium citrate buffered solution for intravenous (IV) or subcutaneous (SC) administration.

Biotechnologies

Biotechnology, the use of living organisms to perform desired tasks, has had an important impact on medicine and biomedical research. The discovery of DNA and its molecular structure has led to the development of recombinant DNA technology, monoclonal antibodies, and human gene therapy, all of which have great potential in the diagnosis and treatment of human diseases.
Biotechnology is based on an understanding of the structure of human cells and their components, such as the nucleus, the cytoplasm, organelles, and the membrane. The nucleus contains most of the cell's genetic information in the form of DNA. DNA molecules are long chains of four different nucleotides that differ in their organic bases (adenine, cytosine, guanine, and thymine). Each DNA molecule consists of two complementary nucleotide chains facing each other.

In the genetic language, which is universal among all organisms, three nucleotides together form a codon, which codes for one amino acid. The DNA region coding for one protein is called a gene. Each human cell contains the complete set of the body's DNA on 46 chromosomes in its nucleus.

Proteins, the products of the genetic information encoded in the DNA, serve as enzymes, structural components, transport molecules, and signaling molecules. The conversion of genetic information into protein products occurs in two steps. During transcription in the nucleus, the DNA nucleotide sequence of one gene is copied into a complementary mRNA molecule. During translation in the cytoplasm, the mRNA serves as the template for protein systhesis.

rDNA technology involves the transfer of genes and production of their proteins in different organisms and in large quantities. The generation of rDNA products isolating the gene of interest; transferring the gene into a host organism, growing large amounts of the host organism, and harvesting and purifying the recombinant product.

To produce recombinant erythropoietin (PROCRIT), Chinese hamster ovarian cells containing the human erythropoietin gene are grown in a large culture before being transferred into a special production medium. After 7 days, the medium is harvested and concentrated, and the recombinant protein is purified, tested, and packaged for use.

Anemia

A variety of different types of anemia exist with various underlying mechanisms. Frequent symptoms for all anemias are fatigue, shortness of breath, exercise intolerance, and pale skin. Anemias can be classified according to their etiology inthypoproliferative anemias and hemolytic anemias/anemia due to blood loss. Other classificatios are based on the size and color of the erythrocytes (morphological classification).

Red blood cell disorders characterized by excessive or abnormal proliferation and differentiation can also have harmful effects for the patients. These disorders include polycythemia and erythroleukemia.

Doctors frequently analyze iron levels in the patients when diagnosing anemia. Common tests include:

  • serum iron

  • total iron-binding capacity

  • transferring saturation

  • serum ferritin

Two types of anemia associated with rapid loss or inadequate intake of nutrients are iron-deficiency anemia and megaloblastic anemia, which is caused by vitamin B12 and/or folic acid deficiency.

Defects in the hemoglobin synthesis can lead to several types of anemia. Thalassemias are caused by the inactivation of one or more of the genes coding for globin. In sickle cell anemia, a defect in the beta-globin genes results in the production of a misshapen globin molecule. Porphyrias are due to defects in heme synthesis. Sideroblastic anemia is caused by a disturbance in the integration of iron into the heme molecule.

Erythropoietin deficiency is at least a contributing factor in three types of anemia:

  • anemia of chronic renal failure

  • anemia of drug-induced renal dysfunction

  • anemia of chronic diseases

Bone marrow dysfuction can also cause anemia. The most common types of anemia in this category are induced by chemotherapy or radiation therapy during cancer treatment; by HIV infection, its consequences, and its treatment; and by chronic diseases in general. Aplastic anemia is caused by a defect in the pluripotent stem cells that leads to a deficiency of all blood cell lines.

PROCRIT currently is used in the treatment of three types of anemia:

  • CRF patients not yet on dialysis

  • HIV-infected patients receiving AZT treatment

  • cancer patients on chemotherapy

In CRF patients not yet on dialysis, PROCRIT restored hematocrit levels to within normal range in up to 87% of the patients. The patients also needed fewer blood transfusions and had improved overall well-being.

In HIV-infected patients with endogenous erythropoietin levels of less than 500 mU/ml, PROCRIT significantly increased the mean hemtocrit. Furthermore, a larger proportion of PROCRIT-treated patients than placebo-treated patients became transfusion independent.

Among anemic cancer patients, both patients receiving cisplatin-containing and cisplatin-free chemotherapy responded to treatment with PROCRIT. Compared with a control group, these patients had higher hematocrit levels at the end of the study and required less transfusions.

Erythropoiesis

Erythrocytes are the most common blood cells. Their primary function is to transport oxygen to all cells in the body. Mature erythrocytes have several very characteristic features: They have lost their nucleus; have a characteristic biconcave, disc-like shape and are packed with hemoglobin. Iron is stored primarily in reticuloendothelial and liver cells. In these cells, iron binds with apoferritin to form ferritin (storage iron). When iron is needed, iron dissociates from ferritin and binds with apotransferrin to form transferrin, a molecule that binds strongly to the receptors of erythroblasts in the bone marrow. Erythroblasts ingest transferrin and use it to synthesize heme. Heme molecules combine with globin proteins to form hemoglobin. At the end of the erythrocyte's life cycle, the iron is released from the hemoglobin and taken up by erythroblasts, monocytes, and macrophages.

Hemoglobin is the carrier molecule for oxygen. In the lungs, where the oxygen concentration is high, oxygen molecules bind to the iron molecules in hemoglobin. In the tissues, where oxygen concentrations are low, the iron releases its bound oxygen and instead takes up carbon dioxide.

Several tests exist to measure the amount and quality of a person's erythrocytes and hemoglobin:

  • blood smear

  • hematocrit

  • hemoglobin concentration

  • reticulocyte count

  • total red blood cell count

  • mean corpuscular volume

  • bone marrow studies

  • red cell distribution width

Erythropoiesis is the process of erythrocyte production in the bone marrow. It requires the presence of the erythropoietin, a protein that is synthesized primarily in the kidneys. When the tissues experience hypoxia, the kidneys can increase their erythropoietin production. Erythropoietin production is reduced when oxygen levels in the tissues rise. Other important factors for erythropoiesis are Vitamin B12 and folic acid, another B-vitamin. A lack of vitamin B12 and folic acid inhibits the continous proliferation of erythrocyte precursors and thus can cause certain kinds of anemia.

Erythropoietin primarily stimulates the proliferation and differentiation of early erythrocyte progenitors, the BFU-E and the CFU-E. Erythropoietin also supports maturation and survival. Subsequent erythrocyte precursors are less dependent on erythorpoietin. The differentiation of erythrocyte precursors is characterized by increasing hemoglobin synthesis and the condensation and expulsion of the nucleus at the reticulocyte stage. The final phase of reticulocyte maturation occurs in the blood.

Erythrocytes have a life span of 120 days, after which they are destroyed by macrophages. Each day, about 1% of the body's erythrocytes are replaced by new reticulocytes.

PRODUCT INSERTS

EPREX® Product Description
Epoetin alfa (EPREX®) is a glycoprotein that is produced by recombinant DNA technology. Epoetin alfa (EPREX®) is available in single-use graduated prefilled syringes containing 2000 IU/0.5 mL, 4000 IU/0.4mL and 10000 IU/1.0 mL.