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Hypertension: In all patients receiving Eprex, blood pressure should be closely monitored and controlled as necessary. Eprex should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension.
It may be necessary to initiate or increase anti-hypertensive treatment during Eprex therapy. If blood pressure cannot be controlled, Eprex treatment should be discontinued.
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during Eprex treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal (see Adverse Reactions).
Pure Red Cell Aplasia: Antibody-mediated PRCA has been reported after epoetin treatment.
Cases also have been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are not approved in the management of anemia associated with hepatitis C.
In chronic renal failure patients developing sudden lack of efficacy, defined by a decrease in hemoglobin (1 to 2 g/dL per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g., iron folate or Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be investigated. If the reticulocyte count corrected for anemia (i.e., the reticulocyte "index") is low (< 20,000/mm3 or < 20,000/mcL or < 0.5%) platelet and white blood cell counts are normal, and if no other cause of loss of effect has been found, anti-erythropoietin antibodies should be determined and a bone marrow examination should be considered for diagnosis of PRCA.
If anti-erythropoietin, antibody-mediated PRCA is suspected, therapy with Eprex should be discontinued immediately. No other ESA therapy should be commenced because of the risk of cross-reaction. Appropriate therapy, such as blood transfusions, may be given to patients when indicated.
General: Eprex should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases.
Eprex should be used with caution in patients with chronic liver failure. The safety of Eprex has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with Eprex.
An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see Adverse Reactions). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral hemorrhage and transient ischemic attacks) have been reported.
The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with Eprex particularly in patients with pre-existing risk factors.
In all patients, hemoglobin concentration should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at hemoglobin concentrations above the range for the indication of use.
The safety and efficacy of Eprex therapy have not been established in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia, thalassemia).
There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with Eprex. This regresses during the course of continued therapy. In addition, thrombocythemia above the normal range has been reported. It is recommended that the platelet count should be regularly monitored during the first 8 weeks of therapy.
Other causes of anemia (iron, folate or Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with Eprex, and when deciding to increase the dose. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to Eprex, adequate iron stores should be assured and iron supplementation should be administered if necessary: For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for adults and 100-200 mg/day orally for pediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferrin saturation is below 20%.
For patients in an autologous predonation program, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting Eprex therapy, and throughout the course of Eprex therapy.
For patients scheduled for major elective orthopedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Eprex therapy. If possible, iron supplementation should be initiated prior to starting Eprex therapy to achieve adequate iron stores.
Very rarely, the initial presentation or exacerbation of porphyria has been observed in Eprex -treated patients. Eprex should be used with caution in patients with porphyria.
Blistering and skin exfoliation reactions including erythema multiforme and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported in a small number of patients treated with Eprex. Discontinue Eprex therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.
The needle cover on the Eprex pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be emphasized that patients should only be switched from one ESA (such as Eprex) to another ESA with the authorization of the treating physician.
Renal Failure Patients: Treatment of symptomatic anemia in adult and pediatric chronic renal failure patients: Chronic renal failure patients being treated with Eprex should have hemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.
In chronic renal failure patients the rate of increase in hemoglobin should be approximately 1 g/dL (0.62 mmol/L)/per month and should not exceed 2 g/dL (1.2 mmol/L)/per month to minimize risks of an increase in hypertension. Dose should be reduced when hemoglobin approaches 12 g/dL.
In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range as recommended under Dosage and Administration. Hemoglobin levels targeted to 13 g/dL or higher may be associated with a higher risk of cardiovascular events, including death.
Patients with chronic renal failure and insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients.
Based on information available to date, the use of Eprex in predialysis end stage renal insufficiency patients does not accelerate the rate of progression of renal insufficiency.
Shunt thromboses have occurred in hemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistula exhibit complications (e.g., stenoses, aneurisms, etc.) Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.
Hyperkalemia has been observed in isolated cases, though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to the appropriate treatment of the hyperkalemia, consideration should be given to ceasing Eprex administration until the serum potassium level has been corrected.
As a result of an increase in packed cell volume, hemodialysis patients receiving Eprex frequently require an increase in heparin dose during dialysis. If heparinization is not optimal, occlusion of the dialysis system is possible.
In some female chronic renal failure patients, menses have resumed following Eprex therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
Cancer Patients: Cancer patients on Eprex should have hemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter.
ESAs are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumor cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of tumors.
In controlled clinical studies, use of Eprex and other ESAs have shown: decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to achieve a hemoglobin concentration level of greater than 14 g/dL (8.7 mmol/L),
shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to a hemoglobin concentration level of 12 to 14 g/dL(7.5 to 8.7 mmol/L),
Another ESA (darbepoietin alfa) increased risk of death when administered to achieve a hemoglobin concentration level of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.
In view of the previously mentioned, the decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors to consider in this assessment include: the type of tumor and its stage; the degree of anemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see Pharmacology: Pharmacodynamics under Actions).
In cancer patients receiving chemotherapy, the 2-3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be considered when assessing whether or not Eprex therapy is appropriate (in particular for patients at risk of transfusion).
HIV-Infected Patients: If HIV-infected patients fail to respond or maintain a response to Eprex, other etiologies including iron deficiency anemia should be considered and evaluated.
Adult Surgery Patients in an Autologous Pre-Donation Program: All special warnings and special precautions associated with autologous blood donation programs, especially routine volume replacement, should be respected in patients being supplemented with Eprex.
Adult Perisurgery Patients (Without Autologous Blood Donation): Good blood management practices should always be used in the perisurgical setting.
Patients scheduled for major elective orthopedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline hemoglobin of > 13 g/dL (8.1 mmol/L), the possibility that Eprex treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline hemoglobin > 13 g/dL (8.1 mmol/L).
The use of Eprex is not recommended in perisurgery patients with a baseline hemoglobin of > 13 g/dL (8.1 mmol/L).
Effects on Ability to Drive and Use Machines: No studies on the effects of Eprex on the ability to drive and use machines have been performed.
Use in Elderly: Among 1051 patients enrolled in the 5 clinical studies of Eprex for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received Eprex and 306 received placebo. Of the 745 patients who received Eprex, 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Eprex in geriatric and younger patients within the 4 studies using the three times per week schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.
Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received Eprex and 125 received placebo. Of the 757 patients who received Eprex, 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the hemoglobin concentration range (see Dosage & Administration).
Insufficient numbers of patients age 65 or older were enrolled in clinical studies for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.
