DESCRIPCION

La eritropoietina alfa es una forma recombiante de la hormona renal eritropoyetina (EPO). Native EPO is a glycosylated protein with a molecular weight of about 36,000 daltons. Epoetin alfa is produced via recombinant technology in a Chinese hamster ovarian cell system. Epoetin alfa is immunologically and biologically indistinguishable from native EPO, and its structure is very similar to the native protein with a molecular weight of 30,400 daltons. The composition and number of carbohydrate chains on epoetin alfa are comparable to those found on the native protein. Development of the recombinant product was begun in 1983 following the discovery of the EPO gene on chromosome 7. Epoetin alfa is FDA-approved for use to treat anemia in chronic renal failure patients, zidovudine-treated HIV patients, and in patients receiving cancer chemotherapy. Epoetin is also FDA-approved to reduce the need for allogeneic blood transfusions in surgery patients. Epoetin alfa first became available for clinical trials in 1985 and the FDA approved it in June 1989.

Mecanismo of Action: Erythropoietin (EPO) is a glycoprotein that regulates the production of red blood cells by stimulating the division and differentiation of committed erythroid progenitor cells in the bone marrow. Epoetin alfa has the same biological activity as native EPO. In adults, almost 90% of EPO is produced in the kidney with the remainder produced by the liver. During fetal development, EPO is produced in the liver, and prior to birthat term, production is transferred to the kidney. Erythropoietin production in the kidney occurs in interstitial cells in the inner cortex that are in immediate proximity to the proximal tubules. More cells are activated as the hematocrit drops. Renal tubular cells may serve as oxygen sensors transmitting signals to the interstitial cells, possibly because they contain large amounts of heme protein that may function as an intracellular oxygen sensor and transducer.[238] Erythropoietin is required for the transformation of the most mature erythroid progenitor cell, erythroid colony-forming unit (CFU-E), to a proerythroblast. In the absence of EPO, this transformation cannot occur and the CFU-E will die. Erythropoietin activates the synthesis of hemoglobin and other proteins found in normal erythroblasts. Erythropoietin also causes a shift of marrow reticulocytes into the circulation. Due to the length of time required for erythropoiesis, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may take up to 6 weeks in some patients. Erythropoietin has little effect on early erythroid progenitor cells, erythroid burst-forming units (BFU-E), whose growth is more dependent upon interleukin-3 and granulocyte-macrophage colony stimulating factor (GM-CSF). The production and activity of EPO is linked in a negative feedback loop, which maintains optimal red cell mass for oxygen transport. There appears to be a plateau of optimal oxygen transport to tissues occurring around hematocrits of 35—55% with significant decreases in oxygen transport above and below these values. Epoetin alfa produces a dose-dependent increase in the hematocrit; an increase of 2% per week may be seen during the initial phase of therapy. The stimulation of erythropoiesis increases the demand for iron, making iron supplementation necessary for many patients. Pharmacokinetics: Epoetin alfa is administered intravenously or subcutaneously. The subcutaneous route produces peak plasma concentrations between 5—24 hours after administration. Although the IV route gives a more rapid peak, the delayed systemic absorption from the subcutaneous route gives a more sustained response. Subcutaneous administration can result in some drug accumulation because of delayed absorption. A dose-dependent response is seen with epoetin alfa doses of 50—300 units/kg three times a week; however, a greater response is not seen at doses > 300 units/kg three times a week. Other factors affecting response to therapy include iron stores, baseline hematocrit, and concurrent medical conditions. As with the endogenous erythropoietin (EPO), epoetin alfa does not appear extravascularly in humans. Whether the drug crosses the placenta or is distributed into breast milk has not been evaluated. Metabolism and elimination of endogenous EPO or epoetin alfa are not fully understood. Epoetin half-life in patients with chronic renal failure after IV administration is 4—13 hours. While the glycosylation of EPO does not affect its binding to target cells, it plays an important role in preventing the rapid clearance of the hormone from the bloodstream. Non-glycosylated erythropoietin has a half-life in vivo of a few minutes. In healthy volunteers, the half-life of epoetin alfa is approximately 20% shorter than the half-life in patients with chronic renal failure. The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that of adults. The drug is not removed by hemodialysis. About 10% of the dose appears to be excreted in the urine.

ndications...Dosage For the treatment of anemia: NOTE: Abbreviations used: Hematocrit (HCT) and hemoglobin (Hgb). •for the treatment of anemia in patients with chronic renal failure (both dialysis-dependent and dialysis-independent patients): NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication. Subcutaneous or intravenous dosage (Initial dosage): Adults and adolescents > 16 years: Initially, 50—100 units/kg IV or SC three times a week. The dose of epoetin alfa should be reduced as the HCT approaches 36% or if the HCT increases by more than 4 points in any 2-week period. Increase the epoetin alfa dose if the hematocrit does not increase by 5—6 points after 8 weeks of therapy. The manufacturer suggested target HCT range is 30—36%, while the National Kidney Foundation recommends a goal HCT between 33—35% (Hgb of 11—12 g/dl). Any clinically significant change in HCT (increase or decrease) following a dosage adjustment may take 2—6 weeks. Dosage adjustments should not be made more frequently than once a month, unless clinically indicated. Following a dose adjustment, the HCT should be determined at least twice weekly for 2—6 weeks. If the HCT remains below or falls below the target range, iron stores should be re-evaluated. Adolescents <= 16 years, children, and infants > 1 month of age on dialysis: 50 units/kg IV or SC three times a week initially. For dosage adjustments, see adult dosage. Adolescents <= 16 years, children, and infants > 1 month of age not on dialysis†: In pediatric patients with chronic renal failure who do not require dialysis, epoetin alfa 50—250 units/kg SC or IV once weekly to three times weekly has been shown to increase Hgb levels and decrease transfusion requirements. For dosage adjustments, see adult dosage. Subcutaneous or intravenous dosage (Maintenance dosage): Adults and adolescents > 16 years: Individualized according to patient response. The median maintenance dose for adult hemodialysis patients is 75 units/kg SC/IV three times weekly (range: 12.5—525 units/kg three times weekly). In adult chronic renal failure patients not on dialysis, doses of 75—150 units/kg/week SC/IV in divided doses have been shown to maintain a HCT of 36—38% for up to 6 months. Over 95% of patients with chronic renal failure respond to epoetin alfa therapy, and virtually all patients are transfusion-independent within 2 months of starting treatment. Adolescents <= 16 years, children, and infants > 1 month of age on dialysis: In pediatric hemodialysis and peritoneal dialysis patients, the median maintenance dose was 167 units/kg/week (49—447 units/kg/week) and 76 units/kg/week (24—323 units/kg/week), respectively, IV or SC administered in divided doses two or three times a week to achieve a target HCT of 30—36%. •for the treatment of zidovudine-induced anemia in HIV-infected patients with circulating endogenous erythropoietin concentrations < 500 mUnits/ml who are receiving a dose of zidovudine <= 4200 mg/week: NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication. NOTE: Patients receiving zidovudine with endogenous serum erythropoietin levels > 500 mUnits/ml are unlikely to respond to epoetin alfa treatment. Subcutaneous or intravenous dosage: Adults: Initially, 100 units/kg SC or IV three times a week for 8—12 weeks. During the initial 8-week period the HCT should be monitored weekly. If response is unsatisfactory after 8 weeks, the dose may be increased by 50—100 units/kg three times a week. Evaluate response every 4—8 weeks and adjust dose as necessary. If a patient has not responded to an epoetin alfa dose of 300 units/kg three times a week, it is unlikely that they will respond to higher doses. Once the desired response is achieved, the dose of epoetin alfa should be titrated to maintain the response. If the HCT exceeds 40%, treatment should be held until the HCT is < 36%. The dose should be reduced by 25% when treatment is resumed and then titrated to desired effect. Adolescents, children, and infants >= 8 months†: Pediatric HIV-infected patients have been treated with epoetin alfa 50—400 units/kg SC or IV 2 to 3 times per week. Increases in Hgb levels and reticulocyte counts, and decreases in or elimination of blood transfusions were observed. •for the treatment of anemia in patients with non-myeloid malignancies where the anemia is due to the effect of concomitantly administered chemotherapy where the chemotherapy is administered for at least 2 months: NOTE: Treatment is not recommended in patients with serum erythropoietin levels > 200 mUnits/ml. Subcutaneous dosage: Adults: 150 units/kg SC 3 times weekly, initially. If the response is not adequate after 8 weeks the dosage may be increased to 300 units/kg SC 3 times weekly. If response is unsatisfactory at a dose of 300 units/kg, it is unlikely that they will respond to higher doses. If the HCT exceeds 40%, the dose should be withheld until the HCT falls to 36%. The dosage should be reduced by 25% when the treatment is resumed. If the initial dose results in a rapid increase in the HCT (e.g., > 4 percentage point increase in any 2 week period), the dose should be reduced. Adolescents, children, and infants > 6 months†: Epoetin alfa dosages of 25—300 units/kg SC or IV 3 to 7 times per week have been given. Increases in Hgb levels and reticulocyte counts, and decreases in or elimination of blood transfusions were observed. •to reduce the need for allogenic blood transfusions in anemic patients (hemoglobin > 10 and <= 13 g/dl) scheduled to undergo elective, noncardiac, nonvascular surgery: NOTE: Epoetin alfa is indicated for patients at high risk for perioperative transfusions with significant, anticipated blood loss. Epoetin alfa is not indicated for anemic patients who are willing to donate autologus blood. Subcutaneous dosage: Adults: 300 IU/kg/day SC for 10 days before surgery, on the day of surgery, and for 4 days after surgery. Alternatively, 600 IU/kg SC once weekly, 21, 14, and 7 days before surgery plus one dose on the day of surgery. All patients should receive adequate iron supplementation during epoetin alfa therapy. •for the treatment of anemia of prematurity†, in combination with iron supplementation: NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication. Subcutaneous dosage: Premature neonates: Various dosage regimens have been used.[2902] [2903] One regimen that has been used successfully is 25—100 units/kg SC 3 times per week. Alternative regimens include 100 units/kg SC 5 times per week or 200 units/kg SC every other day for 10 days. •for the treatment of anemia associated with myelodysplastic syndrome† (MDS): Subcutaneous dosage: Adults: Epoetin alfa 150—300 units/kg SC three times weekly has been shown to improve anemia in about 20% of patients with MDS. When epoetin alfa is given in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte colony stimulating factor (G-CSF), response increases to about 50% of MDS patients. For the treatment of orthostatic hypotension† associated with primary autonomic failure: Subcutaneous dosage: Adults: Although the study was not designed to assess the efficacy of erythropoietin in the treatment of orthostatic hypotension associated with primary autonomic failure, 5 patients demonstrated a beneficial blood pressure response when erythropoietin was administered to treat anemia associated with primary autonomic failure. Four patients received 25 U/kg SC 3 times per week and 1 patient received 50 U/kg SC 3 times per week.[619] Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment: No dosage adjustment needed. †non-FDA-approved indication

Administration Parenteral Administration •Epoetin alfa is administered subcutaneously or intravenously. •Prior to and during epoetin alfa therapy, monitor the patient's iron status including transferrin saturation and serum ferritin. Transferrin saturation should be >= 20% and ferritin should be >= 100 ng/ml. Almost all patients will require iron supplementation during epoetin alfa therapy to maintain adequate iron stores. •Do not shake vial; inactivation of epoetin alfa may occur upon shaking. •Use one single-use vial per dose. Once a syringe has entered a single-dose vial, the sterility of the product can not be guaranteed. Multi-dose vials with preservatives are available. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Immediately discard any unused portion. •Store vials between 2 and 8 degrees C (36 and 46 degrees F); do not freeze. Do not shake. Throw away any unused portion if using a single-dose vial. Multi-dose vials can be kept refrigerated for 21 days once opened. Intravenous injection: •Epoetin alfa may be injected directly into a vein or via the venous return line of the dialysis tubing at the end of a dialysis session. It has been suggested that to prevent adherence to the tubing, epoetin alfa should be injected while blood is still in the IV line, followed by flushing with NS. Subcutaneous injection: •Inject subcutaneously taking care not to inject intradermally.

Contraindications Although it appears epoetin alfa does not have any direct pressor effects, blood pressure may rise during epoetin alfa therapy. Epoetin alfa should not be used in patients with uncontrolled hypertension; hypertension should be controlled prior to beginning epoetin alfa therapy in all patients. Special care should be taken to monitor and aggressively control blood pressure all patients receiving epoetin alfa, especially patients with underlying hypertension or cardiovascular disease. During the early phase of epoetin alfa therapy, up to 25% of patients on dialysis require initiation of, or increases in, antihypertensive therapy. It is recommended that the dose of epoetin alfa be decreased if the hematocrit increase exceeds 4 points in any 2-week period because of the association of excessive rate of rise of hematocrit with an exacerbation of hypertension. Hypertensive patients with HIV who have zidovudine-induced anemia have not shown increases in existing hypertension during epoetin alfa treatment. Epoetin alfa is derived from Chinese hamster ovarian cells and should not be used in patients with known hamster protein hypersensitivity or known albumin hypersensitivity. The multi-dose vial of epoetin alfa contains benzyl alcohol and should not be used in patients with benzyl alcohol hypersensitivity. Benzyl alcohol has been associated with an increased incidence of neurological and other complications, some fatal, in premature neonates. Avoid use of products with benzyl alcohol in premature neonates. The risk of thrombotic events, including myocardial infarction, and mortality are significantly increased in adult hemodialysis patients with ischemic cardiac disease (e.g., angina) or congestive heart failure receiving epoetin alfa therapy with a goal of reaching a normal hematocrit (42%) as compared to a target hematocrit of 30%. Increased mortality was also observed in a controlled trial of epoetin alfa in patients without chronic renal failure who were undergoing coronary artery bypass surgery. Patients with pre-existing cardiac disease should be closely monitored. In patients with thromboembolic disease, the anticipated benefits of epoetin alfa therapy should be weighed against the potential risks. During hemodialysis, patients treated with epoetin alfa may require increased anticoagulant therapy with heparin to prevent clotting of the dialysis machine. The possibility that epoetin alfa may be associated with an increased risk of postoperative thrombotic/vascular events in patients with a hemoglobin > 13 g/dl treated with 300 units/kg of epoetin alfa cannot be excluded. In adult patients on dialysis, there was an increased risk of seizures during the first 90 days of epoetin alfa therapy, when blood pressure and hematocrit increase rapidly, as compared with other timepoints. Seizures have also been reported in other patient populations treated with epoetin alfa, including those with brain tumors. Given the potential for an increased risk of seizures during the first 90 days of therapy, blood pressure and neurologic status should be carefully monitored. Patients should be advised to avoid potentially hazardous activities such as driving or operating machinery. The safety and efficacy of epoetin alfa in patients with a seizure disorder have not been established; these patients should be closely monitored. It is recommended that the dose of epoetin alfa be decreased if the hematocrit increase exceeds 4 points in any 2-week period. Epoetin alfa should be used with caution in patients with porphyria. Exacerbations of porphyria have been reported rarely, but epoetin alfa has not caused increased urinary excretion of porphyrin metabolites in normal volunteers. Patients receiving epoetin alfa should be encouraged to maintain compliance with dietary and dialysis prescriptions, especially as treatment with epoetin alfa increases the patient's sense of well-being and quality of life. During epoetin alfa treatment, hyperkalemia most often occurred in association with poor compliance to medication, diet, and/or dialysis. Treatment with epoetin alfa may result in functional or absolute iron deficiency. Prior to and during epoetin alfa therapy, evaluation of iron stores, including transferrin saturation (serum iron divided by the iron binding capacity) and serum ferritin should be monitored. Transferrin saturation should be at least 20% and the serum ferritin should be at least 100 ng/ml. Virtually all patients will require iron supplementation to increase or maintain transferrin saturation levels that will support erythropoiesis. Anemic patients with iron overload may respond well to the acute phase of epoetin alfa therapy, and may benefit from epoetin alfa therapy and phlebotomy to reduce total iron stores. All surgery patients should receive iron supplementation throughout the course of epoetin alfa therapy. Epoetin alfa is not indicated in patients with iron-deficiency anemia or anemias due to acute or chronic blood loss. The following conditions can interfere with the response to epoetin alfa: acute or chronic infection or inflammation, aluminum overload, cystic fibrosis, erythrocyte enzyme deficiency, folate deficiency, hematological disease (e.g., thalassemia, refractory anemia, or other myelodysplastic disorder), hyperparathyroidism, hypersplenism, occult blood loss, osteitis fibrosa cystica, or vitamin B12 deficiency. To date, epoetin alfa has not been associated with the stimulation of malignant hematologic cell lines. Nevertheless, it should be used with caution in patients with leukemia. The safety and efficacy of epoetin alfa have not been established in patients with sickle cell disease or coagulopathy (i.e., hypercoagulable states). Epoetin alfa is classified as FDA pregnancy risk category C and should be used during pregnancy only when the benefits outweigh the risks of treatment. In some females treated with epoetin alfa, menses have resumed. The possibility of pregnancy and contraceptive considerations should be discussed with the patient. It is not known if epoetin alfa is distributed into breast milk. Although it is similar to an endogenous hormone, breast-feeding should be discouraged during therapy with epoetin alfa.

Interactions No drug interactions with epoetin alfa have been listed to date, but patients receiving multiple drugs concurrently should be monitored carefully for possible interactions. Androgens are known to stimulate erythropoiesis. Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made. It is important that iron stores be repleted before beginning therapy with epoetin alfa. Inadequate iron stores will interfere with the therapeutic response to epoetin alfa. In addition, iron intake may need to be increased during epoetin therapy as existing iron stores are used for erythropoiesis. Iron supplementation (e.g., with either iron dextran; iron salts; polysaccharide-iron complex; sodium ferric gluconate complex) may be required during therapy with epoetin alfa. Concurrent use of desmopressin and epoetin alfa has reduced bleeding time in patients with end-stage renal disease. Animal studies have indicated that probenecid inhibits secretion of endogenous erythropoietin. In addition, amphotericin B has been shown to inhibit endogenous erythropoietin production.[88] It seems unlikely that either of these agents would interfere with the response to epoetin alfa injection.

Adverse Reactions Patients receiving epoetin alfa have developed hypertension. Most commonly, hypertension occurs in chronic renal failure patients receiving dialysis (up to 33%), but it has also been reported rarely in other patient populations. Hypertension has been associated with the acute increase in hematocrit during epoetin alfa therapy, but other factors are involved. A significant increase in blood pressure has been inversely related to the pretreatment hematocrit level, but not the dose of epoetin alfa or baseline blood pressure. Studies have suggested that hypertension may result from a reversal in anemic hypoxic peripheral vasodilation that occurs with improving cardiac output. Increases in blood viscosity have been suggested to play a role, but no significant difference in blood viscosity has been noted in hypertensive versus normotensive patients. Patients with preexisting hypertension may require an increase in antihypertensive therapy. Seizures have occurred during therapy with epoetin alfa. A sudden rise in blood pressure, associated with increased hematocrit, is believed to be the mechanism. There appears to be a higher incidence of seizures during the first 90 days of therapy, occurring in about 2.5% of patients on dialysis receiving epoetin alfa. Seizures have been reported rarely in other patient populations, although some patients had underlying CNS malignancy. Regular evaluations of hematocrit should be made at least twice weekly in patients with chronic renal failure, and once weekly in other patients. If the hematocrit rises by more than 4% in any 2-week period, the dose should be reduced immediately. Hypertensive encephalopathy and seizures have been observed in chronic renal failure patients treated with epoetin alfa. Headache has been reported in up to 16% of patients treated with epoetin alfa. In a trial of epoetin alfa in hemodialysis patients with cardiac disease, mortality was increased in the group randomized to a target hematocrit of 42% versus 30%. The reason for the increased mortality is unknown, however the incidence of non-fatal myocardial infarction (3.1% vs. 2.3%), vascular access thrombosis (39% vs. 29%), and all other thrombotic events including thromboembolism (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. In a study examining the use of epoetin alfa in coronary artery bypass surgery patients, there were 4 deaths in patients treated with epoetin alfa that were associated with a thrombotic/vascular event. Causality has not been established. An increase incidence of deep venous thrombosis (DVT) has been reported in orthopedic surgery patients administered epoetin alfa with a pretreatment hemoglobin > 13 g/dl as compared to similar patients receiving placebo (11% vs. 6%). There was no difference in the incidence of DVT between the two treatment groups in the recommended patient population (i.e., pretreatment hemoglobin > 10 to <= 13 g/dl). Phlebitis and/or thrombophlebitis at the IV infusion site can be a problem during intravenous epoetin alfa therapy. Clotting problems are attributed to increased blood viscosity and a slight rise in platelet count, along with a decrease in bleeding time. Up to 25% of patients report an injection site reaction (e.g., erythema, pruritus, stinging or swelling) following subcutaneous administraton. Flu-like symptoms can occur during initiation of epoetin alfa therapy. Symptoms (e.g., arthralgias, fever, myalgia, or weakness) generally disappear after 2—12 hours. GI effects of epoetin alfa therapy include nausea/vomiting and diarrhea. In studies of epoetin alfa in cancer patients, significantly more patients experienced diarrhea (21% vs. 7%) and edema (17% vs. 1%) during epoetin alfa treatment than placebo; placebo-treated patients experienced significantly more nausea (32% vs. 17%) and trunk pain (16% vs. 3%). Skin rash (unspecified) and urticaria have been observed rarely; there have been no reports of anaphylactic reactions with epoetin alfa. Potentially serious allergic reactions including urticaria in association with bronchospasm or edema have been reported. There has been no evidence of antibody development to erythropoietin, including those patients receiving epoetin alfa for > 4 years. Other adverse reactions reported in patients receiving epoetin alfa include asthenia (7—13%), chest pain (unspecified) (7%), cough (18%), dizziness (7—9%), fatigue (9—25%), paresthesias (11%), shortness of breath (14%), and upper respiratory tract infection (11%). The underlying disease state may have contributed to these adverse reactions.

Epoetin Alfa Epogen®, Procrit®

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2903. Reiter PD, Rosenberg AA, Valuck RJ. Factors associated with successful epoetin alfa therapy in premature infants. Ann Pharmacother 2000;34:433—9.

619. Biaggoni I, Robertson D, Krantz S et al. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994;121;181—6.

88. MacGregor RR, Bennett JE, Erslev AJ. Erythropoietin concentration in amphotericin B-induced anemia. Antimicro Agent Chemo 1978;14:270—3.