Eprex (Epoetin Alfa)

EPREX®

Janssen-Ortho

Epoetin Alfa

Erythropoiesis Regulating Hormone

Action And Clinical Pharmacology: 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. Epoetin alfa is a 165 amino acid glycoprotein manufactured by recombinant DNA technology. 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.

Epoetin alfa is formulated as a sterile, colorless, liquid for i.v. or s.c. administration. The activity of epoetin alfa is determined by comparison of the product to the World Health Organization (WHO) International Reference Standard #2 (10 IU/mL) by both bioassay and radioimmunoassay (RIA). Single-use vials (preservative-free) and single-use prefilled syringes (preservative-free) contain epoetin alfa at a concentration of 2 000, 4 000 or 10 000 IU/mL; multi-use vials (preserved) contain 20 000 IU/mL of epoetin alfa. Multi-use vials also contain 0.9% benzyl alcohol as a preservative.

Chronic Renal Failure (CRF) Patients: Erythropoietin is a glycoprotein which stimulates red blood cell production. Endogenous production of erythropoietin is normally regulated by the level of tissue oxygenation. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis. In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 U/mL and increase up to 100 to 1 000 fold during hypoxia or anemia. In contrast, in patients with chronic renal failure (CRF), production of erythropoietin is impaired, and this erythropoietin deficiency is the primary cause of their anemia.

Epoetin alfa has been shown to stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require regular dialysis. The first evidence of a response to epoetin alfa is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin and hematocrit, usually within 2 to 6 weeks.

Because several days are required for erythroid progenitors to mature and be released into the circulation, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients. Once the hematocrit reaches the target range (30 to 36%), that level can be sustained by epoetin alfa in the absence of iron deficiency and concurrent illnesses.

The rate of hematocrit increase varies between patients and is dependent upon the dose of epoetin alfa, within a therapeutic range of approximately 50 to 300 IU/kg 3 times/week. Other factors affecting the rate and extent of response include availability of iron stores, the baseline hematocrit, and the presence of concurrent medical problems.

I.V. administered epoetin alfa is eliminated at a rate consistent with first order kinetics with a circulating half-life ranging from approximately 4 to 13 hours in patients with CRF. Within the therapeutic dose range, detectable levels of plasma erythropoietin are maintained for at least 24 hours. After s.c. administration of epoetin alfa to patients with CRF, peak serum levels are achieved within 5 to 24 hours after administration and decline slowly thereafter. In comparison with i.v. administration, s.c. administered epoetin alfa is more slowly absorbed and results in lower serum levels which are maintained for 48 hours. The estimated AUC0-48 for s.c. administration is approximately 15% of the AUC0-48 for the same dose given i.v. Despite these differences, epoetin alfa exhibits a dose-related effect on hematological parameters which is independent of route. There is no apparent difference in half-life between patients not on dialysis whose serum creatinine levels were greater than 264 mol/L (3 mg/dL), and patients maintained on dialysis. In normal volunteers, the half-life of i.v. administered epoetin alfa is approximately 20% shorter than the half-life in CRF patients.

Zidovudine-treated/HIV-infected Patients: Response to epoetin alfa in zidovudine-treated/HIV-infected patients is manifested by reduced transfusion requirements and increased hematocrit. Responsiveness to epoetin alfa therapy in HIV-infected patients is dependent upon the endogenous serum erythropoietin levels prior to treatment. Zidovudine-treated/HIV-infected patients with endogenous serum erythropoietin levels £500 mU/mL respond to epoetin alfa therapy. Patients with endogenous serum erythropoietin levels >500 mU/mL do not appear to respond to epoetin alfa therapy. It appears likely that endogenous serum erythropoietin levels in HIV-infected patients receiving zidovudine are related to the severity of the zidovudine-induced damage to erythroid precursors in the bone marrow.

Maximum benefit from epoetin alfa appears to occur when the hematocrit is maintained in the range of 36 to 40%; however, the target hematocrit for zidovudine-treated/HIV-infected patients must be determined on an individual basis.

Cancer Patients: Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents. Epoetin alfa has been shown to increase hematocrit and decrease transfusion requirements (after the first month of therapy) in anemic cancer patients.

In a series of clinical trials enrolling 413 anemic cancer patients who were receiving cyclic chemotherapy (N=289), or not receiving chemotherapy (N=124), approximately 75% of the patients had endogenous serum erythropoietin levels £150 mU/mL, and approximately 5% of patients had endogenous serum erythropoietin levels >500 mU/mL. In patients who were not being treated with chemotherapy with endogenous serum erythropoietin levels £174 mU/mL, the hematocrit response to epoetin alfa (change in hematocrit from baseline to final evaluation) was significantly greater than the corresponding response in placebo-treated patients. In patients who were being treated with cyclic chemotherapeutic regimens, there was not a statistically significant relationship between response to epoetin alfa therapy and the prestudy endogenous serum erythropoietin level; however, treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mU/mL) is not recommended.

Surgery Patients: Use of Epoetin Alfa to Reduce Allogeneic Blood Exposure: Patients undergoing major elective surgery frequently require transfusion of allogeneic blood, both intraoperatively and postoperatively, resulting from blood loss experienced during and after surgery. In patients with a pretreatment hemoglobin of >100 to £130 g/L, epoetin alfa has been shown to decrease the risk of receiving allogeneic transfusions and hasten erythroid recovery (i.e., increased hemoglobin levels, hematocrit levels, and reticulocyte counts).

Combined Use of Epoetin Alfa and Autologous Blood Donation (ABD): Epoetin alfa has been shown to stimulate red blood cell production in order to augment autologous blood collection and to limit the decline in hematocrit in adult patients scheduled for major elective surgery who are not expected to predeposit their complete perioperative blood needs. The greatest effects are observed in patients with low hematocrit (39%).

Indications And Clinical Uses: To elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions. Epoetin alfa is not intended for patients who require immediate correction of severe anemia. Epoetin alfa may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion. Blood pressure should be adequately controlled prior to initiation of epoetin alfa and must be closely monitored and controlled during therapy. Epoetin alfa is not indicated for other specific causes of anemia with established treatments such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding which should be managed appropriately.

Treatment of Anemia of Chronic Renal Failure: In the treatment of anemia associated with chronic renal failure, including patients on dialysis (end-stage renal disease) and patients not on dialysis. Non-dialysis patients with symptomatic anemia considered for therapy should have a hematocrit less than 30%.

Treatment of Anemia in Zidovudine-treated/HIV-infected Patients: For the treatment of transfusion dependent anemia related to therapy with zidovudine in HIV-infected patients. Epoetin alfa is effective in HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is £500 mU/mL and when patients are receiving a dose of zidovudine £4 200 mg/week.

Treatment of Anemia in Cancer Patients: For the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the disease itself, or the effect of concomitantly administered chemotherapy after the first month of therapy.

Surgery Patients: In the following elective surgery regimens: Use of Epoetin Alfa to Reduce Allogeneic Blood Exposure: To treat patients who are undergoing major, elective surgery (including patients who do not wish to or are not eligible to participate in an autologous blood donation program) and have a pretreatment hemoglobin of >100 to 130 g/L. Epoetin alfa is indicated to reduce allogeneic blood transfusions and hasten erythroid recovery in these patients.

Combined Use of Epoetin Alfa and ABD: To facilitate autologous blood collection within a predeposit program and may decrease the risk of receiving allogeneic blood transfusions in patients with hematocrits of 33 to 39%, who are scheduled for major elective surgery and are expected to require more blood than that which can be obtained through autologous blood collection techniques in the absence of epoetin alfa.

Contra-Indications: In patients with: uncontrolled hypertension; known hypersensitivity to mammalian cell-derived products, albumin (human) or any component of the product.

In addition, the 20 000 IU/mL formulation, preserved with benzyl alcohol, is contraindicated in premature infants and newborns.

The use of epoetin alfa in patients scheduled for elective surgery and not participating in an autologous blood donation program, is contraindicated in patients with severe coronary, peripheral arterial, carotid, or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.

Contraindications defined by the guidelines and methods of practice for ABD programs should be respected in patients receiving epoetin alfa.

Manufacturers’ Warnings In Clinical States: All Patients: Multi-use Preserved Formulation: The multi-use preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal.

Hypertension: Patients with uncontrolled hypertension should not be treated with epoetin alfa; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during epoetin alfa therapy, often during the early phase of treatment when the hematocrit is increasing, especially in CRF patients.

For patients who respond to epoetin alfa with a rapid increase in hematocrit (e.g., more than 6 percentage points in any 4-week period), the dose of epoetin alfa should be reduced because of the possible association of excessive rate of rise of hematocrit with an exacerbation of hypertension.

Seizures: Epoetin alfa should be used with caution in patients with a history of seizures. Additional close monitoring of all possible risk factors is advisable if the decision is made to treat patients with a history of seizures with epoetin alfa.

Given the potential for an increased risk of seizures in CRF patients during the first 90 days of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely and CRF patients should be cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery during this period.

It is recommended that the dose of epoetin alfa be decreased if the hematocrit increase exceeds 6 percentage points in any 4-week period.

Thrombotic Events: During hemodialysis, patients treated with epoetin alfa may require increased anticoagulation with heparin to prevent clotting of the artificial kidney. Clotting of the vascular access (AV fistula) has occurred at an annualized rate of about 0.25 events per patient-year on epoetin alfa therapy. Overall, for patients with CRF (whether on dialysis or not), other thrombotic events (e.g., myocardial infarction, cerebrovascular accident, transient ischemic attack) have occurred at an annualized rate of less than 0.04 events per patient-year of epoetin alfa therapy. Patients with pre-existing vascular disease should be monitored closely.

Chronic Renal Failure Patients: In patients with chronic renal failure and clinically evident ischemic heart disease or congestive heart failure, maintenance hematocrit concentration should not exceed the upper limit of the target hematocrit concentration as recommended under Dosage.

Surgery Patients: Combined Use of Epoetin Alfa and ABD: Warnings defined by the guidelines and methods of practice for ABD programs should be respected in patients receiving epoetin alfa.

Precautions: All Patients: General: The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur. If an anaphylactoid reaction occurs, epoetin alfa should be immediately discontinued and appropriate therapy initiated.

The safety and efficacy of epoetin alfa therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

Hypertension: All patients on epoetin alfa should have hematocrit/hemoglobin levels measured at least once a week until a stable level is achieved and periodically thereafter.

Blood pressure should be adequately controlled prior to initiation of epoetin alfa therapy.

In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Particular attention should be paid to the development of unusual headaches or an increase in headaches as a possible warning signal.

It may be necessary to initiate or increase antihypertensive treatment during epoetin alfa therapy. If blood pressure cannot be controlled, epoetin alfa should be discontinued until blood pressure control is re-established.

Thrombotic/Vascular Events: Patients with conditions associated with thrombotic/vascular events should be closely monitored.

Delayed or Diminished Response: Inadequate response to epoetin alfa should prompt an investigation for causative factors. If the patient fails to respond or to maintain a response, the following etiologies should be considered and evaluated: Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see Laboratory Monitoring, Iron Evaluation). Underlying infectious, inflammatory, or malignant processes. Occult blood loss. Underlying hematologic diseases (i.e., thalassemia, refractory anemia, or other myelodysplastic disorders). Vitamin deficiencies: folic acid or vitamin B12. Hemolysis. Aluminum intoxication. Osteitis fibrosa cystica. Inflammatory or traumatic episodes.

Laboratory Tests: Hematology: All patients receiving epoetin alfa should have hematocrit/hemoglobin levels measured once a week until hematocrit/hemoglobin has been stabilized, and measured periodically thereafter. (See CRF Patients, Laboratory Monitoring, Hematology for additional laboratory monitoring in CRF patients.)

There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with epoetin alfa. This regresses during the course of continued therapy. Development of thrombocytosis is very rare. The platelet count should be regularly monitored during the first 8 weeks of therapy.

Although reported in dogs and rats, incidence of bone marrow fibrosis was not increased in dialysis patients treated with epoetin alfa for 12 to 19 months.

Iron Evaluation: In most chronic renal failure, cancer, and HIV-infected patients, the serum ferritin concentrations fall concomitantly with the rise in packed cell volume. Therefore, prior to and during epoetin alfa therapy, the patient’s iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Transferrin saturation should be at least 20%, and serum ferritin levels should be at least 100 ng/mL. Supplemental iron, e.g., oral elemental iron or i.v. iron, is recommended to increase and maintain transferrin saturation to levels that will adequately support epoetin alfa-stimulated erythropoiesis.

All surgery patients being treated with epoetin alfa should receive adequate iron replacement throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores (see Dosage).

Vitamin B12 and Folate Evaluation: Prior to starting epoetin alfa therapy, the patient’s serum vitamin B12 and serum folate should be assessed. A deficiency in vitamin B12 and/or folate may blunt the response and should be investigated as per standard clinical practice.

Use in Patients with Known Porphyria: Exacerbation of porphyria has been observed rarely in CRF patients treated with epoetin alfa. However, epoetin alfa has not caused an increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, epoetin alfa should be used with caution in patients with known porphyria.

Use in Patients with History of Gout: Increased serum uric acid (and phosphorus) levels have been observed in normal volunteers and dialysis independent CRF patients treated with epoetin alfa who experienced a rapid rate of rise of hematocrit. This effect may be related to an increased rate of nucleic acid synthesis in the bone marrow. Consequently, epoetin alfa should be administered with caution to patients with a history of gout.

Drug Interactions: No evidence exists that indicates that treatment with epoetin alfa alters the metabolism of other drugs. However, since cyclosporine is bound by red blood cells there is potential for a drug interaction. If epoetin alfa is given concomitantly with cyclosporine, blood levels of cyclosporine should be monitored and the dose of cyclosporine adjusted as necessary.

Hepatic Dysfunction: The safety of epoetin alfa has not been established in patients with hepatic dysfunction.

Pregnancy : Although epoetin alfa has been shown to have adverse effects in rats when given in doses greater than 5 times the human dose it is not known whether it can affect reproduction capacity or cause fetal harm when administered to pregnant women. Epoetin alfa should be given to a pregnant woman only if potential benefit justifies the potential risk to the fetus.

Lactation : It is not known whether epoetin alfa is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when epoetin alfa is administered to a nursing woman.

Children: The safety and effectiveness of epoetin alfa in children have not been established.

CRF Patients: In some female chronic renal failure patients, menses have resumed following epoetin alfa therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.

Laboratory Monitoring: Hematology: Sufficient time should be allowed to determine a patient’s responsiveness to a dosage of epoetin alfa before adjusting the dose. The hematocrit should be determined weekly until it has stabilized in the target range and the maintenance dose has been established. After any dose adjustment, the hematocrit should also be measured weekly for at least 2 to 6 weeks until it has been determined that the hematocrit has stabilized in response to the dose change. The hematocrit should then be monitored at regular intervals.

A complete blood count with differential and platelet count should be performed regularly. During clinical trials, modest increases were seen in platelets and white blood cell counts. While these changes were statistically significant, they were not clinically significant and the values remained within normal ranges.

In order to avoid reaching the suggested target hematocrit too rapidly, or exceeding the suggested target range (hematocrit of 30 to 36%), the guidelines for dose and frequency of dose adjustments (see Dosage) should be followed.

The elevated bleeding time characteristic of chronic renal failure (CRF) decreases toward normal after correction of anemia in patients treated with epoetin alfa. Reduction of bleeding time also occurs after correction of anemia by transfusion.

Biochemistry: In patients with CRF, serum chemistry values [including blood urea nitrogen (BUN), uric acid, creatinine, phosphorus, and potassium] should be monitored regularly. During clinical trials in patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. In some CRF patients not on dialysis who were treated with epoetin alfa, modest increases in serum uric acid and phosphorus were observed. While changes were statistically significant, the values remained within the ranges normally seen in patients with CRF.

In patients with CRF not on dialysis, renal function and fluid and electrolyte balance should be closely monitored, as an improved sense of well-being may obscure the need to initiate dialysis in some patients. In patients with CRF not on dialysis, placebo-controlled studies of the progression of renal dysfunction over periods of greater than one year have not been completed. In shorter-term trials in patients with CRF not on dialysis, changes in creatinine and creatinine clearance were not significantly different in patients treated with epoetin alfa, compared with placebo-treated patients. Analysis of the slope of 1/serum creatinine vs time plots in these patients indicates no significant change in the slope after the initiation of epoetin alfa therapy.

Dialysis Management: Therapy with epoetin alfa results in an increase in hematocrit and a decrease in plasma volume which could potentially affect dialysis efficiency. In studies to date, the resulting increase in hematocrit did not appear to adversely affect dialyzer function or the efficiency of high flux hemodialysis. During hemodialysis, chronic renal failure patients treated with epoetin alfa may require increased anticoagulation with heparin to prevent clotting of the artificial kidney.

Chronic renal failure patients who are marginally dialyzed may require adjustments in their dialysis prescription. As with all patients on dialysis, the serum chemistry values [including blood urea nitrogen (BUN), creatinine, phosphorus, and potassium] in patients treated with epoetin alfa should be monitored regularly to assure the adequacy of the dialysis prescription.

Diet: As the hematocrit increases and patients experience an improved sense of well-being and quality of life, the importance of compliance with dietary and dialysis prescriptions should be reinforced. In particular, hyperkalemia is not uncommon in patients with CRF.

Predialysis Management: Blood pressure and hematocrit should be monitored in predialysis patients no less frequently than for ESRD patients maintained on dialysis. Renal function and fluid and electrolyte balance should be closely monitored, as an improved sense of well-being may obscure the need to initiate dialysis in some patients.

Based on information to date, the use of epoetin alfa in predialysis patients does not accelerate the rate of progression of renal insufficiency.

Cancer Patients: Growth Factor Potential: Epoetin alfa is a growth factor that primarily stimulates red blood cell production. However, the possibility that epoetin alfa can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded.

Surgery Patients: Use of Epoetin Alfa to Reduce Allogeneic Blood Exposure: Thrombotic/Vascular Events: Patients scheduled for elective surgery should receive adequate antithrombotic prophylaxis as appropriate for the surgical procedure.

In one study in which epoetin alfa was administered in the perioperative period to patients undergoing coronary artery bypass graft surgery and not participating in an autologous blood donation program, there were 7 deaths in the epoetin alfa-treated groups (n=126) and no deaths in the placebo-treated group (n=56). Among the 7 deaths in the epoetin alfa-treated patients, 3 were related to intercurrent infectious episodes and 4 were at the time of therapy (between study day 2 and 8). The percentage of epoetin alfa-treated patients who died was comparable to the mortality rate reported in the literature for patients undergoing coronary artery bypass graft surgery not treated with epoetin alfa. The 4 deaths at the time of therapy (3%) were associated with thrombotic/vascular event and a causative role of epoetin alfa cannot be excluded.

Hypertension: Rarely blood pressure may rise in the perioperative period in patients being treated with epoetin alfa. Therefore, blood pressure should be monitored.

Combined Use of Epoetin Alfa and ABD: Precautions defined by the guidelines and methods of practice for ABD programs should be respected in patients receiving epoetin alfa.

Independent of epoetin alfa treatment, thrombotic and vascular events may occur in surgical patients with underlying cardiovascular disease following repeated phlebotomy. Therefore, routine volume replacement should be performed in such patients in autologous blood donation programs.

Adverse Reactions: All Patients: Hypertension: The most frequent adverse reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. This occurred most commonly in chronic renal failure patients. (See Warnings).

Hypertensive crises including malignant hypertension, encephalopathy-like symptoms (e.g., headaches and confused state) and generalized tonic-clonic seizures have occurred in isolated patients, including previously normotensive patients.

Thrombotic/Vascular Events: Thrombotic/vascular events, such as myocardial ischemia, myocardial infarction, cerebrovascular accidents (cerebral hemorrhage and cerebral infarction), transient ischemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, aneurysms, retinal thrombosis, clotting of vascular access (AV fistula) and clotting of an artificial kidney have been reported in patients receiving epoetin alfa. However, a causal relationship between epoetin alfa therapy and these events has not been established.

In clinical studies conducted in surgery patients with a pretreatment hemoglobin of >100 to 130 g/L (the recommended population), and not participating in an ABD program, the rate of deep venous thrombosis (DVT) was similar among patients treated with epoetin alfa and placebo. However, in patients with a pretreatment hemoglobin of >130 g/L, the rate of DVTs was higher in the group treated with epoetin alfa than in the placebo-treated group, but within the range of that reported in the literature for orthopedic surgery patients (47 to 74% without anticoagulant therapy and 3 to 37% with use of anticoagulant therapy).

In a study examining the use of epoetin alfa in 182 patients scheduled for coronary artery bypass graft surgery, 23% of patients treated with epoetin alfa and 29% treated with placebo experienced thrombotic/vascular events. There were 4 deaths among the patients treated with epoetin alfa that were associated with a thrombotic/vascular event and a causative role of epoetin alfa cannot be excluded.

Thrombocytosis: Thrombocytosis has been observed but its occurrence is rare.

“Flu-like” Symptoms: “Flu-like” signs and symptoms such as dizziness, drowsiness, fever, headaches, joint and muscle pains, and weakness have occurred, especially at the start of treatment.

Allergic Reactions: Skin rashes, eczema, urticaria, pruritus, eosinophilia, and/or angioedema have been observed with epoetin alfa. The cases have generally been mild to moderate in intensity. There have been rare reports of potentially serious reactions associated with respiratory symptoms and hypotension.

Immune Reactions: The development of immune reactions to epoetin alfa or other components of epoetin alfa is rare. Epoetin alfa appears to have minimal potential for inducing antibody formation.

Reactions at Administration Site: Skin reactions at the injection site have been reported in patients treated with epoetin alfa. These reactions occur more frequently in patients receiving s.c. therapy than in patients receiving i.v. therapy. Patients complain of erythema, burning, and pain, usually mild to moderate, around the site of injection.

Seizures: Seizures have been reported in patients treated with epoetin alfa.

CRF Patients: Studies analyzed to date indicate that epoetin alfa is generally well tolerated irrespective of the route of administration. The adverse events reported are frequent sequelae of CRF and are not necessarily attributable to epoetin alfa therapy.

Zidovudine-treated/HIV-infected Patients: Adverse experiences reported in clinical trials with epoetin alfa in zidovudine-treated/HIV-infected patients were consistent with the progression of HIV infection.

Epoetin alfa does not appear to potentiate progression of HIV disease as measured by: incidence of opportunistic infections; mortality; serum p24 antigen levels; or HIV replication in infected cell lines in vitro.

Cancer Patients: Adverse experiences reported in clinical trials with epoetin alfa in cancer patients were consistent with the underlying disease state.

There were no statistically significant differences in the percent of patients treated with epoetin alfa reporting these adverse events compared to the corresponding incidence in placebo-treated patients, except for shortness of breath which occurred in a higher incidence in placebo-treated patients than in patients treated with epoetin alfa.

Surgery Patients: Use of Epoetin Alfa to Reduce Allogeneic Blood Exposure: Adverse events were combined for all groups treated with epoetin alfa and the placebo-treated groups from 4 orthopedic surgery studies where subjects received epoetin alfa at a dose of 300 or 100 IU/kg daily, 600 IU/kg weekly or placebo. Adverse events reported by at least 10% of subjects in any treatment group were as shown in

Similar proportions of patients treated with epoetin alfa and placebo-treated subjects reported each adverse event.

Combined Use of Epoetin Alfa and ABD: The incidence of adverse events was calculated across 5 double-blind, placebo-controlled studies, and 1 single-blind study, combining all patients treated with epoetin alfa (n=402), regardless of dose administered, and all placebo patients (n=242). Adverse experiences with an incidence of 5% in either patients treated with epoetin alfa or placebo-treated patients were as shown in

In general, there were no notable differences between patients treated with epoetin alfa and placebo-treated patients in the incidence of any adverse event.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The maximum amount of epoetin alfa that can be safely administered in single or multiple doses has not been determined. Doses of up to 1 500 IU/kg 3 times/week for 3 to 4 weeks have been administered without any direct toxic effects of epoetin alfa itself. Humans have received epoetin alfa doses as high as 3 000 IU/kg in a single day without acute toxic effects.

Therapy with epoetin alfa can result in polycythemia if the hematocrit is not carefully monitored and the dose appropriately adjusted. If the target range is exceeded, epoetin alfa may be temporarily withheld until the hematocrit returns to the target range; epoetin alfa therapy may then be resumed using a lower dose (see Dosage). If polycythemia is of concern, phlebotomy may be indicated to decrease the hematocrit to within acceptable ranges. Supportive care should be provided for hypertensive or convulsive events that may be related to overdosing with epoetin alfa.

Dosage And Administration: Self-administration and Information to the Patient: In those situations in which the physician determines that a patient can safely and effectively self-administer epoetin alfa, the patient should be instructed as to the proper dosage and administration. The first few doses should be administered under supervision. Following the initial laboratory and clinical assessment, all patients, including those deemed capable of self-administration should be monitored for their response to epoetin alfa, their blood pressure and serum levels, as indicated in the Precautions section. Patients should be referred to the full Information for self-administration section. It is not a disclosure of all possible effects. Patients should be informed of the signs and symptoms of allergic drug reaction and advised of appropriate actions.

If home use is prescribed, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container for the disposal of used syringes and needles should be available to the patient. The full container should be disposed of according to the directions provided by the physician.

CRF Patients: The recommended dose to initiate therapy of epoetin alfa is 50 to 100 IU/kg 3 times/week.

The dosage of epoetin alfa must be individualized to maintain the hematocrit within the suggested target range (30 to 36%). At the physician’s discretion, the suggested target hematocrit range may be expanded to achieve maximal patient benefit.

Epoetin alfa may be given either as an i.v. or s.c. injection. When used i.v., epotein alfa usually has been administered as a slow i.v. bolus 3 times/week. While the administration of epoetin alfa is independent of the dialysis procedure, epoetin alfa solution may be administered into the venous line at the end of the dialysis procedure to obviate the need for additional venous access. Generally the s.c. maintenance dose is approximately 20 to 35% lower than the i.v. maintenance dose. Following the change from i.v. to s.c. route of administration the patient should be monitored carefully to ensure that the hematocrit response is appropriate.

During therapy, hematological parameters should be monitored regularly.

Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels that will adequately support epoetin alfa-stimulated erythropoiesis.

In patients with chronic renal failure and clinically evident ischemic heart disease or congestive heart failure, maintenance hematocrit concentration should not exceed the upper limit of the target hematocrit.

Dose Adjustment: Following epoetin alfa therapy, a period of time is required for erythroid progenitors to mature and be released into circulation resulting in an eventual increase in hematocrit. Additionally, red blood cell survival time affects hematocrit and may vary due to uremia. As a result, the time required to elicit a clinically significant change in hematocrit (increase or decrease) following any dose adjustment may be 2 to 6 weeks.

Dose adjustment should not be made more frequently than once a month, unless clinically indicated. After any dose adjustment, the hematocrit should be determined weekly for at least 2 to 6 weeks (see Precautions, CRF Patients, Laboratory Monitoring).

If the hematocrit is increasing and approaching 36%, the dose should be decreased by approximately 25 IU/kg 3 times/week to maintain the suggested target hematocrit range. If the reduced dose does not stop the rise in hematocrit, and it exceeds 36%, doses should be temporarily withheld until the hematocrit begins to decrease, at which point therapy should be re-initiated at a lower dose.

At any time, if the hematocrit increases by more than 6 percentage points in a 4-week period, the dose should be immediately decreased. After the dose reduction, the hematocrit should be monitored weekly for 2 to 6 weeks, and further dose adjustments should be made (see Maintenance Dose).

If a hematocrit increase of 5 to 6 percentage points is not achieved after an 8-week period and iron stores are adequate (see Delayed or Diminished Response in this section), the dose of epoetin alfa may be increased in increments of 25 IU/kg 3 times/week. Further increases of 25 IU/kg 3 times/week may be added at 4- to 6-week intervals until the desired response is attained.

Maintenance Dose: The maintenance dose must be individualized for each chronic renal failure patient.

If the hematocrit remains below, or falls below, the target range, iron stores should be re-evaluated. If the transferrin saturation is less than 20%, supplemental iron should be administered. If the transferrin saturation is greater than 20%, the dose of epoetin alfa may be increased by 25 IU/kg 3 times/week. Such dose increases should not be made more frequently than once a month, unless clinically indicated, as the response time of the hematocrit to a dose increase can be 2 to 6 weeks. Hematocrit should be measured for 2 to 6 weeks following dose increases.

Delayed or Diminished Response: Over 95% of patients with chronic renal failure responded with clinically significant increases in hematocrit, virtually all patients were transfusion-independent within approximately 2 months of initiation of epoetin alfa therapy.

If a patient fails to respond or maintain a response, other etiologies should be considered and evaluated as clinically indicated (see Precautions).

Zidovudine-treated/HIV-infected Patients: Prior to beginning epoetin alfa therapy, it is recommended that the endogenous serum erythropoietin level be determined (prior to transfusion). Available evidence suggests that patients receiving zidovudine with levels >500 mU/mL are unlikely to respond to therapy with epoetin alfa unless the dose of zidovudine is reduced or temporarily stopped.

Starting Dose: For patients with serum erythropoietin levels 500 mU/mL, the recommended starting dose of epoetin alfa is 100 IU/kg as an i.v. or s.c. injection 3 times weekly for 8 weeks.

Increase Dose: During the dose adjustment phase of therapy, the hematocrit should be monitored weekly. If the response is not satisfactory in terms of reducing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose of epoetin alfa can be increased by 50 to 100 IU/kg 3 times/week. Response should be evaluated every 4 to 8 weeks thereafter and the dose adjusted accordingly by 50 to 100 IU/kg increments 3 times/week. If patients have not responded satisfactorily to an epoetin alfa dose of 300 IU/kg 3 times/week up to month 12 of therapy, further continuation of treatment is not warranted as it is unlikely that they will respond to higher doses of epoetin alfa.

Maintenance Dose: After attainment of the desired response (i.e., reduced transfusion requirements or increased hematocrit), the dose of epoetin alfa should be titrated to maintain the response based on factors such as variations in zidovudine dose and the presence of intercurrent infectious or inflammatory episodes. If the hematocrit exceeds 40%, the dose should be discontinued until the hematocrit drops to 36%. Resume dosing at 25% less than the previous dose and titrate the dose to maintain the desired hematocrit.

Target Hematocrit Range: Maximum benefit from epoetin alfa therapy appears to occur when the hematocrit is maintained in the range of 36 to 40%; however, the target hematocrit for zidovudine-treated/HIV-infected patients must be determined on an individual basis.

Cancer Patients: Epoetin alfa is recommended for the treatment of patients with symptomatic anemia.

Starting Dose: The initial epoetin alfa dose for the treatment of anemia is 150 IU/kg s.c. 3 times/week.

Iron Evaluation: Iron status should be evaluated for all patients prior to and during treatment and iron supplementation should be administered if necessary. Other causes of anemia should also be excluded before instituting therapy with epoetin alfa.

Dose Adjustment: If after 4 weeks of treatment, either the hemoglobin increase is ³10 g/L, or the reticulocyte count increase is 40 000 cells/L above baseline, continue dosing until target hemoglobin is achieved.

If hemoglobin is rising by more than 20 g/L/month, reduce the epoetin alfa dose by about 25%. If the hemoglobin exceeds 140 g/L, discontinue therapy until hemoglobin falls below 120 g/L and then reinstitute epoetin alfa at a dose 25% below the previous dose.

The need to continue epoetin alfa therapy should be re-evaluated periodically, e.g., after completion of chemotherapy.

Endogenous Serum Erythropoietin Levels: In patients not receiving chemotherapy, available evidence suggests that the hemoglobin response in patients treated with epoetin alfa is significantly greater than the corresponding response in placebo-treated patients when the endogenous serum erythropoietin level is 174 mU/mL.

In patients being treated with cyclic chemotherapy, there does not appear to be a significant relationship between the endogenous serum erythropoietin level and response to epoetin alfa therapy. Use of epoetin alfa is not recommended in patients with grossly elevated serum erythropoietin levels (e.g., >200 mU/mL).

Surgery Patients: Use of Epoetin Alfa to Reduce Allogeneic Blood Exposure: The recommended dose regimen is 600 IU/kg s.c. given once weekly for 3 weeks (Days -21, -14, and -7) prior to surgery and on the day of surgery.

If the period prior to surgery is less than 3 weeks, 300 IU/kg s.c. may be given as an alternative dosing regimen for 10 consecutive days prior to surgery, on the day of surgery, and for 4 consecutive days immediately thereafter.

All patients should receive adequate iron replacement. Iron replacement should be initiated no later than the beginning of treatment with epoetin alfa and should continue throughout the course of therapy.

Combined Use of Epoetin Alfa and ABD: Epoetin alfa should be administered twice weekly for 3 weeks prior to surgery if the presurgical predonation interval permits. At each patient visit, a unit of blood is collected and stored for autologous transfusion if the patient has an acceptable hematocrit or hemoglobin for predonation.

The recommended dosage regimen is 600 IU/kg i.v. twice weekly.

Iron status should be evaluated for all patients prior to treatment with epoetin alfa. Iron deficiency, if present, should be corrected. To maintain erythropoiesis, adequate iron supplementation is required beginning as soon as possible and should continue throughout the course of therapy. In anemic patients, the cause of anemia should be explored before starting therapy with epoetin alfa.

Method of Administration: Do not shake. Shaking may denature the glycoprotein, rendering it biologically inactive.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration.

Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing epoetin alfa, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.

S.C. Injection: The maximum volume per injection site should be 1 mL. In case of larger volumes, more than 1 injection site should be used. The injections should be given in the limbs or the anterior abdominal wall. The patient should always alternate the site for each injection.

I.V. Injection: Epoetin alfa should be administered over at least 1 to 5 minutes. A slower injection may be preferable in patients who develop flu-like symptoms.

Multi-use Vial: Contains benzyl alcohol as a preservative and can be re-entered. The date of first entry into the vial should be recorded on the inside flap of the box. Discard 30 days after first entry.

Single-use Vial and Prefilled Syringe: Do not re-enter the vial. Contains no preservative. Discard unused portions.

Do not administer in conjunction with other drug solutions.

The multi-use vial contains 0.9% benzyl alcohol which acts as a local anesthetic and may ameliorate s.c. injection site discomfort.

The phosphate-buffered formulation has been found to mitigate injection site discomfort.

Availability And Storage: Single-use Vials: Phosphate-buffered: Each mL of sterile solution contains: epoetin alfa 4 000 IU. Nonmedicinal ingredients: albumin (human), citric acid, sodium chloride, sodium citrate and water for injection.

Multi-use Vials: Each mL of sterile citrate-buffered solution contains: epoetin alfa 20 000 IU. Nonmedicinal ingredients: albumin (human), benzyl alcohol, citric acid, sodium chloride, sodium citrate and water for injection.

Single-use Syringes: Each mL of sterile phosphate-buffered solution contains: epoetin alfa 2 000, 3 000, 4 000 or 10 000 IU. Nonmedicinal ingredients: albumin (human), sodium chloride, sodium phosphate dibasic dihydrate, sodium phosphate monobasic dihydrate and water for injection. Syringes fill sizes: 1 000 IU/0.5 mL, 2 000 IU/0.5 mL, 3 000 IU /0.3 mL, 4 000 IU/0.4 mL and 10 000 IU/1.0 mL.

Store at 2 to 8°C. Do not freeze or shake. Protect from exposure to light. Multi-use vials should be discarded 30 days after first entry.

EPREX® Janssen-Ortho Epoetin Alfa Erythropoiesis Regulating Hormone

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