Epoetin alfa
DRUG DESCRIPTION
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. EPOGEN® (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.
EPOGEN® is formulated as a sterile, colorless liquid in an isotonic sodium chloride/sodium citrate buffered solution or a sodium chloride/sodium phosphate buffered solution for intravenous (IV) or subcutaneous (SC) administration.
Single-dose, Preservative-free Vial: Each 1 mL of solution contains 2000, 3000, 4000 or 10,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). This formulation contains no preservative.
Single-dose, Preservative-free Vial: 1 mL (40,000 Units/mL). Each 1 mL of solution contains 40,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 1.2 mg sodium phosphate monobasic monohydrate, 1.8 mg sodium phosphate dibasic anhydrate, 0.7 mg sodium citrate, 5.8 mg sodium chloride, and 6.8 mcg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). This formulation contains no preservative.
Multidose, Preserved Vial: 2 mL (20,000 Units, 10,000 Units/mL). Each 1 mL of solution contains 10,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3).
Multidose, Preserved Vial: 1 mL (20,000 Units/mL). Each 1 mL of solution contains 20,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3).
INDICATIONS
Treatment of Anemia of Chronic Renal Failure Patients
EPOGEN® is indicated for the treatment of anemia associated with CRF, including patients on dialysis and patients not on dialysis. EPOGEN® is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients.
Non-dialysis patients with symptomatic anemia considered for therapy should have a hemoglobin less than 10 g/dL.
EPOGEN® is not intended for patients who require immediate correction of severe anemia. EPOGEN® may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion.
Prior to initiation of therapy, the patient's iron stores should be evaluated. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Blood pressure should be adequately controlled prior to initiation of EPOGEN® therapy, and must be closely monitored and controlled during therapy.
Treatment of Anemia in Zidovudine-treated HIV-infected Patients
EPOGEN® is indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients. EPOGEN® is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients. EPOGEN® is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately. EPOGEN® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.
EPOGEN®, at a dose of 100 Units/kg TIW, is effective in decreasing the transfusion requirement and increasing the red blood cell level of anemic, HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is ? 500 mUnits/mL and when patients are receiving a dose of zidovudine ? 4200 mg/week.
Treatment of Anemia in Cancer Patients on Chemotherapy
EPOGEN® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether EPOGEN® increases mortality or decreases progression-free/recurrence-free survival are ongoing.
EPOGEN® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
EPOGEN® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of EPOGEN® on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).
EPOGEN® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).
EPOGEN® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.
Reduction of Allogeneic Blood Transfusion in Surgery Patients
EPOGEN® is indicated for the treatment of anemic patients (hemoglobin > 10 to ? 13 g/dL) who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.17-19 EPOGEN® is not indicated for anemic patients who are willing to donate autologous blood (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events.
Chronic Renal Failure Patients
The recommended range for the starting dose of EPOGEN® is 50 to 100 Units/kg TIW for adult patients. The recommended starting dose for pediatric CRF patients on dialysis is 50 Units/kg TIW. Individualize dosing to achieve and maintain hemoglobin levels between 10-12 g/dL. The dose of EPOGEN® should be reduced as the hemoglobin approaches 12 g/dL or increases by more than 1 g/dL in any 2-week period. If hemoglobin excursions outside the recommended range occur, the EPOGEN® dose should be adjusted as described below.
EPOGEN® may be given either as an IV or SC injection. In patients on hemodialysis, the IV route is recommended (see WARNINGS: Pure Red Cell Aplasia). While the administration of EPOGEN® is independent of the dialysis procedure, EPOGEN® may be administered into the venous line at the end of the dialysis procedure to obviate the need for additional venous access. In adult patients with CRF not on dialysis, EPOGEN® may be given either as an IV or SC injection.
Patients who have been judged competent by their physicians to self-administer EPOGEN® without medical or other supervision may give themselves either an IV or SC injection. The table below provides general therapeutic guidelines for patients with CRF:
Individually titrate to achieve and maintain hemoglobin levels between 10 to 12 g/dL.
Starting Dose:
Adults
Pediatric Patients
50 to 100 Units/kg TIW; IV or SC
50 Units/kg TIW; IV or SC
Increase Dose by 25% If: 1. Hemoglobin is < 10 g/dL and has not increased by 1 g/dL after 4 weeks of therapy or
2. Hemoglobin decreases below 10 g/dL
Reduce Dose by 25% When: 1. Hemoglobin approaches 12 g/dL or,
2. Hemoglobin increases > 1 g/dL in any 2-week period
During therapy, hematological parameters should be monitored regularly. Doses must be individualized to ensure that hemoglobin is maintained at an appropriate level for each patient.
For patients whose hemoglobin does not attain a level within the range of 10 to 12 g/dL despite the use of appropriate EPOGEN® dose titrations over a 12-week period:
do not administer higher EPOGEN® doses and use the lowest dose that will maintain a hemoglobin level sufficient to avoid the need for recurrent RBC transfusions,
evaluate and treat for other causes of anemia (see PRECAUTIONS: Lack or Loss of Response), and
thereafter, hemoglobin should continue to be monitored and if responsiveness improves, EPOGEN® dose adjustments should be made as described above; discontinue EPOGEN® if responsiveness does not improve and the patient needs recurrent RBC transfusions.
Pretherapy Iron Evaluation: Prior to and during EPOGEN® 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 ferritin should be at least 100 ng/mL. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels that will adequately support erythropoiesis stimulated by EPOGEN®.
Dose Adjustment: The dose should be adjusted for each patient to achieve and maintain hemoglobin levels between 10 to 12 g/dL.
Increases in dose should not be made more frequently than once a month. If the hemoglobin is increasing and approaching 12 g/dL, the dose should be reduced by approximately 25%. If the hemoglobin continues to increase, dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25% below the previous dose. If the hemoglobin increases by more than 1 g/dL in a 2-week period, the dose should be decreased by approximately 25%.
If the increase in the hemoglobin is less than 1 g/dL over 4 weeks and iron stores are adequate (see PRECAUTIONS: Laboratory Monitoring), the dose of EPOGEN® may be increased by approximately 25% of the previous dose. Further increases may be made at 4-week intervals until the specified hemoglobin is obtained.
Maintenance Dose: The maintenance dose must be individualized for each patient on dialysis. In the US phase 3 multicenter trial in patients on hemodialysis, the median maintenance dose was 75 Units/kg TIW, with a range from 12.5 to 525 Units/kg TIW. Almost 10% of the patients required a dose of 25 Units/kg, or less, and approximately 10% of the patients required more than 200 Units/kg TIW to maintain their hematocrit in the suggested target range. In pediatric hemodialysis and peritoneal dialysis patients, the median maintenance dose was 167 Units/kg/week (49 to 447 Units/kg per week) and 76 Units/kg per week (24 to 323 Units/kg/week) administered in divided doses (TIW or BIW), respectively to achieve the target range of 30% to 36%.
If the transferrin saturation is greater than 20%, the dose of EPOGEN® may be increased. Such dose increases should not be made more frequently than once a month, unless clinically indicated, as the response time of the hemoglobin to a dose increase can be 2 to 6 weeks. Hemoglobin should be measured twice weekly for 2 to 6 weeks following dose increases. In adult patients with CRF not on dialysis, the dose should also be individualized to maintain hemoglobin levels between 10 to 12 g/dL. EPOGEN® doses of 75 to 150 Units/kg/week have been shown to maintain hematocrits of 36% to 38% for up to 6 months.
Lack or Loss of Response: If a patient fails to respond or maintain a response, an evaluation for causative factors should be undertaken (see WARNINGS: Pure Red Cell Aplasia, PRECAUTIONS: Lack or Loss of Response, and PRECAUTIONS: Iron Evaluation). If the transferrin saturation is less than 20%, supplemental iron should be administered.
Zidovudine-treated HIV-infected Patients
Prior to beginning EPOGEN®, it is recommended that the endogenous serum erythropoietin level be determined (prior to transfusion). Available evidence suggests that patients receiving zidovudine with endogenous serum erythropoietin levels > 500 mUnits/mL are unlikely to respond to therapy with EPOGEN®.
In zidovudine-treated HIV-infected patients the dosage of EPOGEN® should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not to exceed the upper safety limit of 12 g/dL.
Starting Dose: For adult patients with serum erythropoietin levels ? 500 mUnits/mL who are receiving a dose of zidovudine ? 4200 mg/week, the recommended starting dose of EPOGEN® is 100 Units/kg as an IV or SC injection TIW for 8 weeks. For pediatric patients, see PRECAUTIONS: Pediatric Use.
Increase Dose: During the dose adjustment phase of therapy, the hemoglobin should be monitored weekly. If the response is not satisfactory in terms of reducing transfusion requirements or increasing hemoglobin after 8 weeks of therapy, the dose of EPOGEN® can be increased by 50 to 100 Units/kg TIW. Response should be evaluated every 4 to 8 weeks thereafter and the dose adjusted accordingly by 50 to 100 Units/kg increments TIW. If patients have not responded satisfactorily to an EPOGEN® dose of 300 Units/kg TIW, it is unlikely that they will respond to higher doses of EPOGEN®.
Maintenance Dose: After attainment of the desired response (ie, reduced transfusion requirements or increased hemoglobin), the dose of EPOGEN® 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 hemoglobin exceeds the upper safety limit of 12 g/dL, the dose should be discontinued until the hemoglobin drops below 11 g/dL. The dose should be reduced by 25% when treatment is resumed and then titrated to maintain the desired hemoglobin.
Cancer Patients on Chemotherapy
Although no specific serum erythropoietin level has been established which predicts which patients would be unlikely to respond to EPOGEN® therapy, treatment of patients with grossly elevated serum erythropoietin levels (eg, > 200 mUnits/mL) is not recommended. Therapy should not be initiated at hemoglobin levels ? 10 g/dL. The hemoglobin should be monitored on a weekly basis in patients receiving EPOGEN® therapy until hemoglobin becomes stable. The dose of EPOGEN® should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion (see recommended Dose Modifications, below).
Recommended Dose: The initial recommended dose of EPOGEN® in adults is 150 Units/kg SC TIW or 40,000 Units SC Weekly. The initial recommended dose of EPOGEN® in pediatric patients is 600 Units/kg IV weekly. Discontinue EPOGEN® following the completion of a chemotherapy course (see BOXED WARNINGS: Cancer).
Dose Modification
TIW Dosing
Starting Dose:
Adults
Reduce Dose by 25% when: 150 Units/kg SC TIW
Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-week period.
Withhold Dose if: Hemoglobin exceeds a level needed to avoid transfusion. Restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required.
Increase Dose to 300 Units/kg TIW if: Response is not satisfactory (no reduction in transfusionrequirements or rise in hemoglobin) after 4 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.
Discontinue: If after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.
Weekly Dosing
Starting Dose:
Adults 40,000 Units SC
Pediatrics 600 Units/kg IV (maximum 40,000 Units)
Reduce Dose by 25% when: Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-weeks.
Withhold Dose if: Hemoglobin exceeds a level needed to avoid transfusion and restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required.
Increase Dose if:
For Adults: 60,000 Units SC Weekly
For Pediatrics: 900 Units/kg IV (maximum 60,000 Units) if: Response is not satisfactory (no increase in hemoglobin by ? 1 g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.
Discontinue: If after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.
Surgery Patients
Prior to initiating treatment with EPOGEN® a hemoglobin should be obtained to establish that it is > 10 to ? 13 g/dL.17 The recommended dose of EPOGEN® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
An alternate dose schedule is 600 Units/kg EPOGEN® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.18
All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with EPOGEN® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS).
Preparation And Administration Of Epogen®
Do not shake. It is not necessary to shake EPOGEN®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive.
Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing EPOGEN®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.
Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions.
Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8° C after initial entry and between doses. Discard 21 days after initial entry.
Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free EPOGEN® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of EPOGEN® containing benzyl alcohol.
SIDE EFFECTS
Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving EPOGEN® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.
There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to EPOGEN®, in controlled clinical trials.
Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading.
Chronic Renal Failure Patients
In double-blind, placebo-controlled studies involving over 300 patients with CRF, the events reported in greater than 5% of patients treated with EPOGEN® during the blinded phase were:
Percent of Patients Reporting EventEvent Patients Treated With EPOGEN®
(n = 200) Placebo-treated Patients
(n = 135)
Hypertension 24% 19%
Headache 16% 12%
Arthralgias 11% 6%
Nausea 11% 9%
Edema 9% 10%
Fatigue 9% 14%
Diarrhea 9% 6%
Vomiting 8% 5%
Chest Pain 7% 9%
Skin Reaction (Administration Site) 7% 12%
Asthenia 7% 12%
Dizziness 7% 13%
Clotted Access 7% 2%
Significant adverse events of concern in patients with CRF treated in double-blind, placebo-controlled trials occurred in the following percent of patients during the blinded phase of the studies:
Seizure 1.1% 1.1%
CVA/TIA 0.4% 0.6%
MI 0.4% 1.1%
Death 0% 1.7%
In the US EPOGEN® studies in adult patients on dialysis (over 567 patients), the incidence (number of events per patient-year) of the most frequently reported adverse events were: hypertension (0.75), headache (0.40), tachycardia (0.31), nausea/vomiting (0.26), clotted vascular access (0.25), shortness of breath (0.14), hyperkalemia (0.11), and diarrhea (0.11). Other reported events occurred at a rate of less than 0.10 events per patient per year.
Events reported to have occurred within several hours of administration of EPOGEN® were rare, mild, and transient, and included injection site stinging in dialysis patients and flu-like symptoms such as arthralgias and myalgias.
In all studies analyzed to date, EPOGEN® administration was generally well-tolerated, irrespective of the route of administration.
Pediatric CRF Patients: In pediatric patients with CRF on dialysis, the pattern of most adverse events was similar to that found in adults. Additional adverse events reported during the double-blind phase in > 10% of pediatric patients in either treatment group were: abdominal pain, dialysis access complications including access infections and peritonitis in those receiving peritoneal dialysis, fever, upper respiratory infection, cough, pharyngitis, and constipation. The rates are similar between the treatment groups for each event.
Hypertension: Increases in blood pressure have been reported in clinical trials, often during the first 90 days of therapy. On occasion, hypertensive encephalopathy and seizures have been observed in patients with CRF treated with EPOGEN®. When data from all patients in the US phase 3 multicenter trial were analyzed, there was an apparent trend of more reports of hypertensive adverse events in patients on dialysis with a faster rate of rise of hematocrit (greater than 4 hematocrit points in any 2-week period). However, in a double-blind, placebo-controlled trial, hypertensive adverse events were not reported at an increased rate in the group treated with EPOGEN® (150 Units/kg TIW) relative to the placebo group.
Seizures: There have been 47 seizures in 1010 patients on dialysis treated with EPOGEN® in clinical trials, with an exposure of 986 patient-years for a rate of approximately 0.048 events per patient-year. However, there appeared to be a higher rate of seizures during the first 90 days of therapy (occurring in approximately 2.5% of patients) when compared to subsequent 90-day periods. The baseline incidence of seizures in the untreated dialysis population is difficult to determine; it appears to be in the range of 5% to 10% per patient-year.34-36
Thrombotic Events: In clinical trials where the maintenance hematocrit was 35 ± 3% on EPOGEN®, clotting of the vascular access (A-V shunt) has occurred at an annualized rate of about 0.25 events per patient-year, and other thrombotic events (eg, myocardial infarction, cerebral vascular accident, transient ischemic attack, and pulmonary embolism) occurred at a rate of 0.04 events per patient-year. In a separate study of 1111 untreated dialysis patients, clotting of the vascular access occurred at a rate of 0.50 events per patient-year. However, in CRF patients on hemodialysis who also had clinically evident ischemic heart disease or congestive heart failure, the risk of A-V shunt thrombosis was higher (39% vs 29%, p < 0.001), and myocardial infarctions, vascular ischemic events, and venous thrombosis were increased, in patients targeted to a hematocrit of 42 ± 3% compared to those maintained at 30 ± 3% (see WARNINGS).
In patients treated with commercial EPOGEN®, there have been rare reports of serious or unusual thromboembolic events including migratory thrombophlebitis, microvascular thrombosis, pulmonary embolus, and thrombosis of the retinal artery, and temporal and renal veins. A causal relationship has not been established.
Allergic Reactions: There have been no reports of serious allergic reactions or anaphylaxis associated with EPOGEN® administration during clinical trials. Skin rashes and urticaria have been observed rarely and when reported have generally been mild and transient in nature.
There have been rare reports of potentially serious allergic reactions including urticaria with associated respiratory symptoms or circumoral edema, or urticaria alone. Most reactions occurred in situations where a causal relationship could not be established. Symptoms recurred with rechallenge in a few instances, suggesting that allergic reactivity may occasionally be associated with EPOGEN® therapy. If an anaphylactoid reaction occurs, EPOGEN® should be immediately discontinued and appropriate therapy initiated.
Zidovudine-treated HIV-infected Patients
In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse events with an incidence of ? 10% in either patients treated with EPOGEN® or placebo-treated patients were:
Percent of Patients Reporting EventEvent Patients Treated With EPOGEN®
(n = 144) Placebo-treated Patients
(n = 153)
Pyrexia 38% 29%
Fatigue 25% 31%
Headache 19% 14%
Cough 18% 14%
Diarrhea 16% 18%
Rash 16% 8%
Congestion, Respiratory 15% 10%
Nausea 15% 12%
Shortness of Breath 14% 13%
Asthenia 11% 14%
Skin Reaction, Medication Site 10% 7%
Dizziness 9% 10%
In the 297 patients studied, EPOGEN® was not associated with significant increases in opportunistic infections or mortality.23 In 71 patients from this group treated with EPOGEN® at 150 Units/kg TIW, serum p24 antigen levels did not appear to increase.25 Preliminary data showed no enhancement of HIV replication in infected cell lines in vitro.23
Peripheral white blood cell and platelet counts are unchanged following EPOGEN® therapy.
Allergic Reactions: Two zidovudine-treated HIV-infected patients had urticarial reactions within 48 hours of their first exposure to study medication. One patient was treated with EPOGEN® and one was treated with placebo (EPOGEN® vehicle alone). Both patients had positive immediate skin tests against their study medication with a negative saline control. The basis for this apparent pre-existing hypersensitivity to components of the EPOGEN® formulation is unknown, but may be related to HIV-induced immunosuppression or prior exposure to blood products.
Seizures: In double-blind and open-label trials of EPOGEN® in zidovudine-treated HIV-infected patients, 10 patients have experienced seizures.23 In general, these seizures appear to be related to underlying pathology such as meningitis or cerebral neoplasms, not EPOGEN® therapy.
Cancer Patients on Chemotherapy
In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with EPOGEN® or placebo-treated patients were as indicated below:
Percent of Patients Reporting EventEvent Patients Treated With EPOGEN®
(n = 63) Placebo-treated Patients
(n = 68)
Pyrexia 29% 19%
Diarrhea 21%* 7%
Nausea 17%* 32%
Vomiting 17% 15%
Edema 17%* 1%
Asthenia 13% 16%
Fatigue 13% 15%
Shortness of Breath 13% 9%
Parasthesia 11% 6%
Upper Respiratory Infection 11% 4%
Dizziness 5% 12%
Trunk Pain 3%* 16%
* Statistically significant
Although some statistically significant differences between patients being treated with EPOGEN® and placebo-treated patients were noted, the overall safety profile of EPOGEN® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to EPOGEN®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of EPOGEN® was consistent with the progression of advanced cancer.
Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with EPOGEN® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms.
Surgery Patients
Adverse events with an incidence of ? 10% are shown in the following table:
Percent of Patients Reporting EventEvent Patients Treated With EPOGEN® 300 U/kg
(n = 112)a Patients Treated With EPOGEN® 100 U/kg
(n = 101)a Placebo-treated Patients
(n = 103)a Patients Treated With EPOGEN® 600 U/kg
(n = 73)b Patients Treated With EPOGEN® 300 U/kg
(n = 72)b
Pyrexia 51% 50% 60% 47% 42%
Nausea 48% 43% 45% 45% 58%
Constipation 43% 42% 43% 51% 53%
Skin Reaction, Medication Site 25% 19% 22% 26% 29%
Vomiting 22% 12% 14% 21% 29%
Skin Pain 18% 18% 17% 5% 4%
Pruritus 16% 16% 14% 14% 22%
Insomnia 13% 16% 13% 21% 18%
Headache 13% 11% 9% 10% 19%
Dizziness 12% 9% 12% 11% 21%
Urinary Tract Infection 12% 3% 11% 11% 8%
Hypertension 10% 11% 10% 5% 10%
Diarrhea 10% 7% 12% 10% 6%
Deep Venous Thrombosis 10% 3% 5% 0%c 0%c
Dyspepsia 9% 11% 6% 7% 8%
Anxiety 7% 2% 11% 11% 4%
Edema 6% 11% 8% 11% 7%
a Study including patients undergoing orthopedic surgery treated with EPOGEN® or placebo for 15 days
b Study including patients undergoing orthopedic surgery treated with EPOGEN® 600 Units/kg weekly x 4 or 300 Units/kg daily x 15
c Determined by clinical symptoms
Thrombotic/Vascular Events: In three double-blind, placebo-controlled orthopedic surgery studies, the rate of deep venous thrombosis (DVT) was similar among Epoetin alfa and placebo-treated patients in the recommended population of patients with a pretreatment hemoglobin of > 10 g/dL to ? 13 g/dL.17,19,26 However, in 2 of 3 orthopedic surgery studies the overall rate (all pretreatment hemoglobin groups combined) of DVTs detected by postoperative ultrasonography and/or surveillance venography was higher in the group treated with Epoetin alfa than in the placebo-treated group (11% vs. 6%). This finding was attributable to the difference in DVT rates observed in the subgroup of patients with pretreatment hemoglobin > 13 g/dL.
In the orthopedic surgery study of patients with pretreatment hemoglobin of > 10 g/dL to ? 13 g/dL which compared two dosing regimens (600 Units/kg weekly x 4 and 300 Units/kg daily x 15), 4 subjects in the 600 Units/kg weekly EPOGEN® group (5%) and no subjects in the 300 Units/kg daily group had a thrombotic vascular event during the study period.18
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 Epoetin alfa-treated patients that were associated with a thrombotic/vascular event (see WARNINGS).
WARNINGS
Pediatrics
Risk in Premature Infants
The multidose 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.
Adults
Increased Mortality, Serious Cardiovascular and Thromboembolic Events
Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. EPOGEN® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.
In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).40
Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to EPOGEN® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%.37 Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents.
In a randomized controlled study (referred to as Cancer Study 1 - the 'BEST' study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).43
A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the 'BEST' and 'ENHANCE' studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.41
An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events). In a randomized controlled study (referred to as the 'SPINE' study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION).
Increased mortality was also observed in a randomized placebo-controlled study of EPOGEN® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to EPOGEN® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events.42 ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence
Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).
Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional ControlStudy / Tumor / (n) Hemoglobin Target Achieved Hemoglobin (Median Q1,Q3) Primary Endpoint Adverse Outcome for ESA-containing Arm
Chemotherapy
Cancer Study 1
Metastatic breast cancer (n=939) 12-14 g/dL 12.9 g/dL
12.2, 13.3 g/dL 12-month overall survival Decreased 12-month survival
Cancer Study 2
Lymphoid malignancy (n=344) 13-15 g/dL (M)
13-14 g/dL (F) 11.0 g/dL
9.8, 12.1 g/dL Proportion ofpatients achieving a hemoglobin response Decreased overall survival
Cancer Study 3
Early breast cancer (n=733) 12.5-13 g/dL 13.1 g/dL
12.5, 13.7 g/dL Relapse-free and overall survival Decreased 3 yr. relapse-free and overall survival
Cancer Study 4
Cervical Cancer (n=114) 12-14 g/dL 12.7 g/dL
12.1, 13.3 g/dL Progression-free and overall survival and locoregional control Decreased 3 yr. progression-free and overall survival and locoregional control
Radiotherapy Alone
Cancer Study 5
Head and neck cancer (n=351) ? 15 g/dL (M)
? 14 g/dL (F) Not available Locoregional progression-free survival Decreased 5-year locoregional progression-free survival Decreased overall survival
Cancer Study 6
Head and neck cancer (n=522) 14-15.5 g/dL Not available Locoregional disease control Decreased locoregional disease control
No Chemotherapy or Radiotherapy
Cancer Study 7
Non-small cell lung cancer (n=70) 12-14 g/dL Not available Quality of life Decreased overall survival
Cancer Study 8
Non-myeloid malignancy (n=989) 12-13 g/dL 10.6 g/dL
9.4, 11.8 g/dL RBC transfusions Decreased overall survival
Decreased overall survival
Cancer Study 1 (the 'BEST' study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).43
Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.
Decreased progression-free survival and overall survival
Cancer Study 3 (the 'PREPARE' study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfa-treated arm compared to the control arm.
Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).
Cancer Study 5 (the 'ENHANCE' study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).38
Decreased locoregional control
Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with EPOGEN®. This has been reported predominantly in patients with CRF receiving EPOGEN® by subcutaneous administration. Any patient who develops a sudden loss of response to EPOGEN®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold EPOGEN® and other erythropoietic proteins. Contact Amgen (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies. EPOGEN® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).
Albumin (Human)
EPOGEN® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Chronic Renal Failure Patients
Hypertension: Patients with uncontrolled hypertension should not be treated with EPOGEN®; blood pressure should be controlled adequately before initiation of therapy. Although there do not appear to be any direct pressor effects of EPOGEN®, blood pressure may rise during EPOGEN® therapy. During the early phase of treatment when the hematocrit is increasing, approximately 25% of patients on dialysis may require initiation of, or increases in, antihypertensive therapy. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with EPOGEN®.
Special care should be taken to closely monitor and aggressively control blood pressure in patients treated with EPOGEN®. Patients should be advised as to the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control by initiation of appropriate measures, the hemoglobin may be reduced by decreasing or withholding the dose of EPOGEN®. A clinically significant decrease in hemoglobin may not be observed for several weeks.
It is recommended that the dose of EPOGEN® be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period, because of the possible association of excessive rate of rise of hemoglobin with an exacerbation of hypertension. In CRF patients on hemodialysis with clinically evident ischemic heart disease or congestive heart failure, the dose of EPOGEN® should be carefully adjusted to achieve and maintain hemoglobin levels between 10-12 g/dL (see WARNINGS: Mortality, Serious Cardiovascular and Thromboembolic Events and DOSAGE AND ADMINISTRATION: Chronic Renal Failure Patients).
Seizures: Seizures have occurred in patients with CRF participating in EPOGEN® clinical trials.
In adult patients on dialysis, there was a higher incidence of seizures during the first 90 days of therapy (occurring in approximately 2.5% of patients) as compared with later timepoints.
Given the potential for an increased risk of seizures during the first 90 days of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Patients should be cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery during this period.
While the relationship between seizures and the rate of rise of hemoglobin is uncertain, it is recommended that the dose of EPOGEN® be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period.
Thrombotic Events: During hemodialysis, patients treated with EPOGEN® may require increased anticoagulation with heparin to prevent clotting of the artificial kidney (see ADVERSE REACTIONS for more information about thrombotic events).
Other thrombotic events (eg, myocardial infarction, cerebrovascular accident, transient ischemic attack) have occurred in clinical trials at an annualized rate of less than 0.04 events per patient year of EPOGEN® therapy. These trials were conducted in adult patients with CRF (whether on dialysis or not) in whom the target hematocrit was 32% to 40%. However, the risk of thrombotic events, including vascular access thrombosis, was significantly increased in adult patients with ischemic heart disease or congestive heart failure receiving EPOGEN® therapy with the goal of reaching a normal hematocrit (42%) as compared to a target hematocrit of 30%. Patients with pre-existing cardiovascular disease should be monitored closely.
Zidovudine-treated HIV-infected Patients
In contrast to CRF patients, EPOGEN® therapy has not been linked to exacerbation of hypertension, seizures, and thrombotic events in HIV-infected patients. However, the clinical data do not rule out an increased risk for serious cardiovascular events