Epogen Epoetin Alfa

EPOGENÒ

(Epoetin alfa)

FOR INJECTION

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. EPOGENÒ (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.

EPOGENÒ 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).

REFERENCES

1. Egrie JC, Strickland TW, Lane J, et al. Characterization and Biological Effects of Recombinant Human Erythropoietin. Immunobiol. 1986;72:213-224.

INDICATIONS AND USAGE

Treatment of Anemia of Chronic Renal Failure Patients

EPOGENÒ is indicated for the treatment of anemia associated with CRF, including patients on dialysis (ESRD) and patients not on dialysis. EPOGENÒ 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.

EPOGENÒ is not intended for patients who require immediate correction of severe anemia. EPOGENÒ 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 EPOGENÒ therapy, and must be closely monitored and controlled during therapy.

EPOGENÒ should be administered under the guidance of a qualified physician (see DOSAGE AND ADMINISTRATION).

Treatment of Anemia in Zidovudine-treated HIV-infected Patients

EPOGENÒ is indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients. EPOGENÒ 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.

EPOGENÒ 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.

EPOGENÒ, 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

EPOGENÒ is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. EPOGENÒ is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months. EPOGENÒ 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, which should be managed appropriately.

Reduction of Allogeneic Blood Transfusion in Surgery Patients

EPOGENÒ is indicated for the treatment of anemic patients (hemoglobin>10 to £ 13 g/dL) scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.18-20 EPOGENÒ is indicated for patients at high risk for perioperative transfusions with significant, anticipated blood loss. EPOGENÒ is not indicated for anemic patients who are willing to donate autologous blood. The safety of the perioperative use of EPOGENÒ has been studied only in patients who are receiving anticoagulant prophylaxis.

CLINICAL EXPERIENCE: RESPONSE TO EPOGENÒ

Chronic Renal Failure Patients

Response to EPOGENÒ was consistent across all studies. In the presence of adequate iron stores (see IRON EVALUATION), the time to reach the target hematocrit is a function of the baseline hematocrit and the rate of hematocrit rise.

The rate of increase in hematocrit is dependent upon the dose of EPOGENÒ administered and individual patient variation. In clinical trials at starting doses of 50 to 150 Units/kg TIW, adult patients responded with an average rate of hematocrit rise. of:

Starting Dose
Hematocrit Increase
(TIW IV)
Points/Day
Points/2 Weeks
50 Units/kg
0.1 1
1.5
100 Units/kg
0.18
2.5
150 Units/kg
0.25
3.5

Over this dose range, approximately 95% of all patients responded with a clinically significant increase in hematocrit, and by the end of approximately 2 months of therapy virtually all patients were transfusion-independent. Changes in the quality of life of adult patients treated with EPOGENÒ were assessed as part of a phase 3 clinical trial.5,8 Once the target hematocrit (32% to 38%) was achieved, statistically significant improvements were demonstrated for most quality of life parameters measured, including energy and activity level, functional ability, sleep and eating behavior, health status, satisfaction with health, sex life, well-being, psychological effect, life satisfaction, and happiness. Patients also reported improvement in their disease symptoms. They showed a statistically significant increase in exercise capacity (V02 max), energy, and strength with a significant reduction in aching, dizziness, anxiety, shortness of breath, muscle weakness, and leg cramps.8,21

Adult Patients on Dialysis: Thirteen clinical studies were conducted, involving IV administration to a total of 1010 anemic patients on dialysis for 986 patient-years of EPOGENÒ therapy. In the three largest of these clinical trials, the median maintenance dose necessary to maintain the hematocrit between 30% to 36% was approximately 75 Units/kg TIW. In the US multicenter phase 3 study, approximately 65% of the patients required doses of 100 Units/kg TIW, or less, to maintain their hematocrit at approximately 35%. Almost 10% of patients required a dose of 25 Units/kg, or less, and approximately 10% required a dose of more than 200 Units/kg TIW to maintain their hematocrit at this level.

A multicenter unit dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered EPOGENÒ subcutaneously for approximately 109 patient-years of experience. Patients responded to EPOGENÒ administered SC in a manner similar to patients receiving IVadministration.22

Pediatric Patients on Dialysis: One hundred twenty-eight children from 2 months to 19 years of age with CRF requiring dialysis were enrolled in 4 clinical studies of EPOGENÒ. The largest study was a placebo-controlled, randomized trial in 113 children with anemia (hematocrit £ 27%) undergoing peritoneal dialysis or hemodialysis. The initial dose of EPOGENÒ was 50 Units/kg IV or SC TIW. The dose of study drug was titrated to achieve either a hematocrit of 30% to 36% or an absolute increase in hematocrit of 6 percentage points over baseline.

At the end of the initial 12 weeks, a statistically significant rise in mean hematocrit (9.4% vs 0.9%) was observed only in the EPOGENÒ arm. The proportion of children achieving a hematocrit of 30%, or an increase in hematocrit of 6 percentage points over baseline, at any time during the first 12 weeks was higher in the EPOGENÒ arm (96% vs 58%). Within 12 weeks of initiating EPOGENÒ therapy, 92.3% of the pediatric patients were transfusion-independent as compared to 65.4% who received placebo.

Among patients who received 36 weeks of EPOGENÒ, hemodialysis patients required a higher median maintenance dose (167 Units/kg/week [n = 28] vs 76 Units/kg/week [n = 36]) and took longer to achieve a hematocrit of 30% to 36% (median time to response 69 days vs 32 days) than patients undergoing peritoneal dialysis.

Patients With CRF Not Requiring Dialysis

Four clinical trials were conducted in patients with CRF not on dialysis involving 181 patients treated with EPOGENÒ for approximately 67 patient-years of experience. These patients responded to EPOGENÒ therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when EPOGENÒ was administered by either an IV or SC route, with similar rates of rise of hematocrit when EPOGENÒ was administered by either route. Moreover, EPOGENÒ doses of 75 to 150 Units/kg per week have been shown to maintain hematocrits of 36% to 38% for up to 6 months. Correcting the anemia of progressive renal failure will allow patients to remain active even though their renal function continues to decrease.23-24

Zidovudine-treated HIV-infected Patients

EPOGENÒ has been studied in four placebo-controlled trials enrolling 297 anemic (hematocrit < 30%) HIV-infected (AIDS) patients receiving concomitant therapy with zidovudine (all patients were treated with Epoetin alfa manufactured by Amgen Inc). In the subgroup of patients (89/125 EPOGENÒ and 88/130 placebo) with prestudy endogenous serum erythropoietin levels £ 500 mUnits/mL, EPOGENÒ reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group.25 Among those patients who required transfusions at baseline, 43% of patients treated with EPOGENÒ versus 18% of placebo-treated patients were transfusion-independent during the second and third months of therapy. EPOGENÒ therapy also resulted in significant increases in hematocrit in comparison to placebo. When examining the results according to the weekly dose of zidovudine received during month 3 of therapy, there was a statistically significant (p < 0.003) reduction in transfusion requirements in patients treated with EPOGENÒ (n = 51) compared to placebo treated patients (n = 54) whose mean weekly zidovudine dose was £ 4200 mg/week.25

Approximately 17% of the patients with endogenous serum erythropoietin levels £ 500 mUnits/mL receiving EPOGENÒ in doses from 100 to 200 Units/kg TIW achieved a hematocrit of 38% without administration of transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose prestudy endogenous serum erythropoietin levels were > 500 mUnits/mL, EPOGENÒ therapy did not reduce transfusion requirements or increase hematocrit, compared to the corresponding responses in placebo-treated patients.

In a 6 month open-label EPOGENÒ study, patients responded with decreased transfusion requirements and sustained increases in hematocrit and hemoglobin with doses of EPOGENÒ up to 300 Units/kg TIW.25-27

Responsiveness to EPOGENÒ therapy may be blunted by intercurrent infectious/inflammatory episodes and by an increase in zidovudine dosage. Consequently, the dose of EPOGENÒ must be titrated based on these factors to maintain the desired erythropoietic response.

Cancer Patients on Chemotherapy

Adult Patients

Three-Times Weekly (TIW) Dosing

EPOGENÒ administered TIW has been studied in a series of six placebo-controlled, double-blind trials that enrolled 131 anemic cancer patients receiving EPOGENÒ or matching placebo. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Patients were randomized to EPOGENÒ 150 Units/kg or placebo subcutaneously TIW for 12 weeks in each study.

The results of the pooled data from these six studies are shown in the table below. Because of the length of time required for erythropoiesis and red cell maturation, the efficacy of EPOGENÒ (reduction in proportion of patients requiring transfusions) is not manifested until 2 to 6 weeks after initiation of EPOGENÒ.

Proportion of Patients Transfused During Chemotherapy
(Efficacy Populationa)

Chemotherapy Regimen
On Studyb
During Months 2 and 3c
EPOGENÒ
Placebo
EPOGENÒ
Placebo
Regimens without cisplatin
44% (15/34)
44% (16/36)
21% (6/29)
33% (11/33)
Regimens containing cisplatin
50% (14/28)
63% (19/30)
23% (5/22)d
56% (14/25)
Combined
47% (29/62)
53% (35/66)
22%(11/51)d
43% (25/58)

a Limited to patients remaining on study at least 15 days (1 patient excluded from EPOGENÒ, 2 patients excluded from placebo).
b Includes all transfusions from day 1 through the end of study.
c Limited to patients remaining on study beyond week 6 and includes only transfusions during weeks 5-12.
d Unadjusted 2-sided p < 0.05

Intensity of chemotherapy in the above trials was not directly assessed, however the degree and timing of neutropenia was comparable across all trials. Available evidence suggests that patients with lymphoid and solid cancers respond similarly to EPOGENÒ therapy, and that patients with or without tumor infiltration of the bone marrow respond similarly to EPOGENÒ therapy.

Weekly (QW) Dosing

EPOGENÒ was also studied in a placebo-controlled, double-blind trial utilizing weekly dosing in a total of 344 anemic cancer patients. In this trial, 61 (35 placebo arm and 26 in the EPOGENÒ arm) patients were treated with concomitant cisplatin containing regimens and 283 patients received concomitant chemotherapy regimens that did not contain cisplatinum. Patients were randomized to EPOGENÒ 40,000 Units weekly (n = 174) or placebo (n = 170) SC for a planned treatment period of 16 weeks. If hemoglobin had not increased by > 1 g/dL, after 4 weeks of therapy or the patient received RBC transfusion during the first 4 weeks of therapy, study drug was increased to 60,000 Units weekly. Forty-three percent of patients in the Epoetin alfa group required and increase in EPOGENÒ dose to 60,000 Units weekly. 25

Results demonstrated that EPOGENÒ therapy reduced the proportion of patients transfused in day 29 through week 16 of the study as compared to placebo. Twenty-five patients (14%) in the EPOGENÒ group received transfusions compared to 48 patients (28%) in the placebo group (p = 0.0010) between day 29 and week 16 or the last day on study.

Comparable intensity of chemotherapy for patients enrolled in the two study arms was suggested by similarities in mean dose and frequency of administration for the 10 most commonly administered chemotherapy agents, and similarity in the incidence of changes in chemotherapy during the trial in the two arms.

Pediatric Patients

The safety and effectiveness of EPOGENÒ were evaluated in a randomized, double-blind, placebo-controlled, multicenter study in anemic patients ages 5 to 18 receiving chemotherapy for the treatment of various childhood malignancies. Two hundred twenty-two patients were randomized (1:1) to EPOGENÒ or placebo. EPOGENÒ was administered at 600 Units/kg (maximum 40,000 Units) intravenously once per week for 16 weeks. If hemoglobin had not increased by 1 g/dL after the first 4-5 weeks of therapy, EPOGENÒ was increased to 900 Units/kg (maximum 60,000 Units). Among the EPOGENÒ-treated patients 60% required dose escalation to 900 Units/kg/week.

The effect of EPOGENÒ on transfusion requirements is shown in the table below:

Percentage of Patients Transfused:
On Study1
After 28 Days
Post-Randomization
EPOGENÒ
(n=111)
Placebo
(n=111)
EPOGENÒ
(n=111)
Placebo
(n=111)
65% (72)
77 % (86)
51%(57)2
69% (77)

1 Includes all transfusions from day 1 through the end of study
2 Adjusted 2 sided p <0.05

There was no evidence of an improvement in health-related quality of life in patients receiving EPOGENÒ as compared to those receiving placebo.

Surgery Patients

EPOGENÒ has been studied in a placebo-controlled, double-blind trial enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ³ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Based on previous studies which demonstrated that pretreatment hemoglobin is a predictor of risk of receiving transfusion, 20,28 patients were stratified into one of three groups based on their pretreatment hemoglobin [£10 (n = 2), > 10 to £13 (n = 96), and > 13 to £ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg EPOGENÒ, 100 Units/kg EPOGENÒ or placebo by SC injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery.18 All patients received oral iron and a low-dose post-operative warfarin regimen.18

Treatment with EPOGENÒ 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic transfusion in patients with a pretreatment hemoglobin of > 10 to £ 13; 5/31 (16%) of EPOGENÒ 300 Units/kg, 6/26 (23%) of EPOGENÒ 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused.18 There was no significant difference in the number of patients transfused between EPOGENÒ (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to £15 g/dL hemoglobin stratum. There were too few patients in the £10 g/dL group to determine if EPOGENÒ is useful in this hemoglobin strata. In the > 10 to £13 g/dL pretreatment stratum, the mean number of units transfused per EPOGENÒ-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with EPOGENÒ.18

EPOGENÒ was also studied in an open-label, parallel-group trial enrolling 145 subjects with a pretreatment hemoglobin level of ³ 10 to £ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program.19 Subjects were randomly assigned to receive one of two SC dosing regimens of EPOGENÒ (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery and for 4 days after surgery). All subjects received oral iron and appropriate pharmacologic anticoagulation therapy.

From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than observed in the 300 Units/kg daily group.19 The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 x 106/mm3) compared to the daily group (0.17 x 106/mm) Mean hemoglobin levels were similar for the two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group].19 The mean number of units transfused per subject was approximately 0.3 units in both treatment groups.

DOSAGE AND ADMINISTRATION

Chronic Renal Failure Patients

The recommended range for the starting dose of EPOGENÒ 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. The dose of EPOGENÒ should be reduced as the hemoglobin approaches 12 g/dL or increases by more than 1 g/dL in any 2-week period. The dosage of EPOGENÒ must be individualized to maintain the hemoglobin within the suggested target range. At the physician's discretion, the suggested target hemoglobin range may be expanded to achieve maximal patient benefit.

EPOGENÒ 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) and EPOGENÒ usually has been administered as an IV bolus TIW. While the administration of EPOGENÒ is independent of the dialysis procedure, EPOGENÒ 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, EPOGENÒ may be given either as an IV or SC injection.

Patients who have been judged competent by their physicians to self-administer EPOGENÒ 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:

Starting Dose:
         Adults
         Pediatric Patients
50 to 100 Units/kg TIW; IV or SC
50 Units/kg TIW; IV or SC
Reduce Dose When:
1. Hgb approaches 12 g/dL or,
2. Hgb increases >1 g/dL in any 2-week period
Increase Dose If:
Hgb does not increase by 2 g/dL after 8 weeks of therapy, and hgb is below suggested target range
Maintenance Dose:
Individually titrate
Suggested Target Hgb Range:
10 g/dL to 12 g/dL

During therapy, hematological parameters should be monitored regularly (see LABORATORY MONITORING).

Pretherapy Iron Evaluation: Prior to and during EPOGENÒ 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 EPOGENÒ.

Dose Adjustment: The dose should be adjusted for each patient to achieve and maintain a target hemoglobin not to exceed 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 EPOGENÒ 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), week), respectively to achieve the target range of 30% to 36%.

If the hemoglobin remains below, or falls below, the suggested 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 EPOGENÒ 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 maintenance dose must also be individualized. EPOGENÒ 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).

Zidovudine-treated HIV-infected Patients

Prior to beginning EPOGENÒ, 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 EPOGENÒ.

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 EPOGENÒ 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 EPOGENÒ 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 EPOGENÒ dose of 300 Units/kg TIW, it is unlikely that they will respond to higher doses of EPOGENÒ.

Maintenance Dose: After attainment of the desired response (ie, reduced transfusion requirements or increased hemoglobin), the dose of EPOGENÒ 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 13 g/dL, the dose should be discontinued until the hemoglobin drops to 12 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 EPOGENÒ therapy, treatment of patients with grossly elevated serum erythropoietin levels (eg, > 200 mUnits/mL) is not recommended. The hemoglobin should be monitored on a weekly basis in patients receiving EPOGENÒ therapy until hemoglobin becomes stable. The dose of EPOGENÒ should be titrated to maintain the desired hemoglobin (See recommended Dose Modifications, below).

Recommended Dose: The initial recommended dose of EPOGENÒ in adults is 150 Units/kg SC TIW or 40,000 Units SC Weekly. For pediatric patients, weekly dosing is recommended.

Dose Modification

TIW Dosing
Starting Dose:
         Adults
150 Units/kg SC TIW
Reduce Dose by 25% when:
1. Hgb approaches 12 g/dL or,
2. Hgb increases >1 g/dL in any 2-week period
Withhold Dose if:
Hgb exceeds 13 g/dL, until the hemoglobin falls to 12 g/dL, and restart dose at 25% below the previous dose
Increase Dose to 300 Units/kg TIW if:
response is not satisfactory [no reduction in transfusion requirements or rise in hemoglobin] after 8 weeks
Suggested Target Hgb Range:
10 g/dL to 12 g/dL
Weekly Dosing
Starting Dose:
Adults
Pediatrics
40,000 Units SC
600 Units/kg IV (maximum 40,000 Units)
Reduce Dose by 25% when:
Hgb exceeds 12 g/dL or increases >1 g/dL in any 2-weeks
Withhold Dose if:
Hgb exceeds 13 g/dL, until the hemoglobin falls to 12 g/dL, and restart dose at 25% below the previous dose
Increase Dose if:
response is not satisfactory (no increase in hemoglobin by ³ 1g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to:
Adults: 60,000 Units SC Weekly
Pediatrics: 900 Units/kg IV (maximum 60,000 Units)
Suggested Target Hgb Range:
10 g/dL to 12 g/dL

Surgery Patients

Prior to initiating treatment with EPOGENÒ a hemoglobin should be obtained to establish that it is > 10 to £ 13 g/dL.18 The recommended dose of EPOGENÒ 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 EPOGENÒ subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.19

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

PREPARATION AND ADMINISTRATION OF EPOGENÒ

1. Do not shake. It is not necessary to shake EPOGENÒ. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive.

2. 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.

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

4. 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.

5. Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free EPOGENÒ 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 EPOGENÒ containing benzyl alcohol.

HOW SUPPLIED

EPOGENÒ, containing Epoetin alfa, is available in the following packages:

1 mL Single-dose, Preservative-free Solution

2000 Units/mL (NDC 55513-126-10)
3000 Units/mL (NDC 55513-267-10)
4000 Units/mL (NDC 55513-148-10)
10,000 Units/mL (NDC 55513-144-10)
40,000 Units/mL (NDC 55513-823-10)

Supplied in dispensing packs containing 10 single-dose vials.

2 mL Multidose, Preserved Solution

10,000 Units/mL (NDC 55513-283-10)

1 mL Multidose, Preserved Solution

20,000 Units/mL (NDC 55513-478-10)

Supplied in dispensing packs containing 10 multidose vials.

STORAGE

Store at 2° to 8° C (36° to 46° F). Do not freeze or shake.

This product's label may have been revised after this insert was used in production. For further product information and the current package insert, please visit www.amgen.com or call our medical information department toll-free at 1-800-77 AMGEN (1-800-772-6436).

REFERENCES

5. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human Erythropoietin in Anemic Patients with End-Stage Renal Disease. Ann Intem Med. 1989;111:992-1000.
8. Evans RW, Rader B, Manninen DL, et al. The Quality of Life of Hemodialysis Recipients Treated with Recombinant Human Erythropoietin. JAMA. 1990;263:825-830.
18. deAndrade JR and Jove M. Baseline Hemoglobin as a Predictor of Risk of Transfusion and Response to Epoetin alfa in Orthoperdic Surgery Patients. Am. J. of Orthoped. 1996;25 (8):533-542.
19. Goldberg MA and McCutchen JW. A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin alfa in Patients Undergoing Major Orthopedic Surgery. Am. J. of Orthoped. 1996;25 (8):544-552.
20. Faris PM and Ritter MA. The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopedic Operation. J. Bone and Joint surgery. 1996;78-A:62-72.
21. Lundin AP, Akerman MJH, Chesler RM, et al. Exercise in Hemodialysis Patients after Treatment with Recombinant Human Erythropoietin. Nephron. 1991 ;58:315-319.
22. Amgen Inc., data on file.
23. Eschbach JW, Kelly MR, Haley NR, et al. Treatment of the Anemia of Progressive Renal Failure with Recombinant Human Erythropoietin. NEJM. 1989;321:158-163.
24. The US Recombinant Human Erythropoietin Predialysis Study Group. Double-Blind, Placebo-Controlled Study of the Therapeutic Use of Recombinant Human Erythropoietin for Anemia Associated with Chronic Renal Failure in Predialysis Patients. Am J Kid Dis. 1991 ;18:50-59.
25. Ortho Biologics, Inc., data on file.
26. Danna RP, Rudnick SA, Abels RI. Erythropoietin Therapy for the Anemia Associated with AIDS and AIDS Therapy and Cancer. In: MB Garnick, ed. Erythropoietin in Clinical Applications - An International Perspective. New York, NY: Marcel Dekker; 1990:301-324.
27. Fischl M, Galpin JE, Levine JD, et al. Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine. NEJM. 1990;322: 1488-1493.
28. Laupacis A. Effectiveness of Perioperative Recombinant Human Eyrthropoietin in Elective Hip Replacement. Lancet. 1993;341: 1228-1232.

Manufactured by:
Amgen Manufacturing, Limited,
a subsidiary of Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Ó 1989, 2005 Amgen Inc. All rights reserved.
FDA rev date: 5/11/06

EPOGENÒ
(EE - PO - JEN)

EPOETIN ALFA

PATIENT INFORMATION

INFORMATION FOR PATIENTS AND THEIR CAREGIVERS

Please read this patient package insert before you start taking EPOGENÒ. This is a summary and not a replacement for a careful discussion with your doctor. This patient package insert does not include all available information about EPOGENÒ. Only your doctor can prescribe EPOGENÒ and determine if it is right for you. If you wish to change or discontinue your treatment, please talk to your doctor first.

What is EPOGENÒ?

EPOGENÒ is a protein similar to human erythropoietin (ee-rith-row-po-eh-tin), a substance your body produces naturally to stimulate the bone marrow to produce oxygen-carrying red blood cells.

What is EPOGENÒ used for?

EPOGENÒ is used to treat anemia (a lower than normal number of oxygen-carrying red blood cells). People with anemia may feel tired or may feel a lack of energy. They may also experience weakness, dizziness, difficulty with concentration, shortness of breath, chest pain, and feeling cold all the time. Your doctor has prescribed EPOGENÒ to treat your anemia. If your body responds to EPOGENÒ, your symptoms may improve. EPOGEN ( may be used to treat your anemia if you have:

· chronic kidney disease (who may or may not be on dialysis)

· one of the most common types of cancer and are receiving chemotherapy,

· certain scheduled surgeries (in order to reduce the need for blood transfusions or if you are at risk for significant blood loss)

· HIV and take a medicine called Zidovudine (AZT).

How does it work?

EPOGENÒ increases or replaces the amount of erythropoietin in the body to stimulate the bone marrow to make more of the oxygen-carrying red blood cells.

The effectiveness of EPOGENÒ is monitored by a blood test that measures the number of red blood cells in your body. Your doctor may refer to the results of these tests as your hemoglobin and/or hematocrit. The rise in the number of red blood cells (hemoglobin and/or hematocrit) may result in the need for fewer blood transfusions and may improve the symptoms of your anemia. The increase in the number of red blood cells usually takes about 2 to 6 weeks. The amount of time it takes, and the dose of EPOGENÒ that is needed to increase the number of red blood cells, is different for each patient.

EPOGEN Ò is not for the treatment of anemia solely due to other factors such as low levels of iron or a certain type of vitamin B, the breakdown of red blood cells, or gastrointestinal bleeding. Your doctor will determine the cause of your anemia and discuss this with you.

Who should not take EPOGENÒ?

You should NOT take EPOGENÒ if you have:

· Uncontrolled high blood pressure (hypertension)

· Allergies to products made from animals or mammalian cells

· Allergies to Albumin (human)

· Previous allergic reactions to any of EPOGENÒs ingredients. See the list of ingredients in EPOGENÒ at the end of the leaflet

Talk to your doctor, if you are not sure if you have these conditions or if you have any questions about this information.

What should I tell my doctor before taking EPOGENÒ?

Tell your doctor about all your health conditions and all the medicines you take including prescription, non-prescription, vitamins, supplements, and herbals. Be sure to tell your doctor if you have:

· heart disease

· high blood pressure

· any history of seizures

· blood disorders (sickle cell anemia or clotting disorders)

· are pregnant or nursing

· are planning to become pregnant

Talk to your doctor, if you are not sure if you have these conditions or if you have any questions about this information.

Your doctor or another healthcare professional may monitor your blood pressure and blood iron levels before starting your therapy and while you are taking EPOGENÒ. You or your caregiver may also be instructed to monitor your own blood pressure everyday and to report any changes outside of the guidelines that your doctor has given you. When the number of red blood cells increases, your blood pressure can also increase, so your doctor may prescribe some new or additional blood pressure medication. You may also be instructed to have certain laboratory tests, such as hemoglobin, hematocrit or blood iron level measurements. Also, your doctor may prescribe iron for you to take. Be sure to follow your doctor's orders.

What are the possible side effects of EPOGENÒ?

The most common side effects you may have when taking EPOGENÒ are:

· Increased blood pressure
· Vomiting
· Headache
· Swelling in your legs and arms
· Body aches
· Shortness of breath
· Diarrhea
· Fever
· Nausea

Some side effects are more common depending on the reason why you are taking EPOGENÒ. Talk to your doctor for more information about your side effects; report them to your doctor right away.

Other, more serious side effects may occur such as seizures, blood clots, or allergic reactions. If you experience any of these or any other side effect, report them to your doctor right away.

EPOGENÒ has other side effects that are not listed here. For a complete list, talk to your doctor. If you notice any side effects not mentioned in this leaflet, or if you have any concerns about a side effect you may be having, talk to your doctor.

Call your doctor right away if:

· You take more than the amount prescribed

· You have certain symptoms that may be a sign of a more serious problem. Contact your doctor right away if you have symptoms of:

· Severe anemia: unusual tiredness and lack of energy. This can happen if your body makes antibodies against EPOGENÒ. Antibodies to EPOGENÒ can block or reduce your body's ability to make red blood cells, causing severe anemia.

· Serious allergic reaction: rash over the whole body, shortness of breath, wheezing, a drop in blood pressure, swelling around the mouth and or eyes, fast pulse, or sweating.

· Seizure: confusion, dizziness, loss of consciousness. Seizures are more likely during the first 90 days of therapy. You should consider avoiding potentially hazardous activities such as driving or operating heavy machinery during this period.

· Increased blood pressure: your doctor or caregiver may monitor your blood pressure more frequently or increase or start medicine to control your blood pressure.

· Blood clots: pain and/or swelling in the legs or worsening in shortness of breath.

· Blood clots in your hemodialysis vascular access port.

How should I take EPOGENÒ?

What important information do home dialysis patients and/or their caregivers need to know about giving EPOGENÒ injections?

In those situations where your doctor has determined that you, as a home dialysis patient, and/or your caregiver can administer EPOGENÒ at home, always follow the instructions of your doctor concerning the dose, how to administer and how often to administer EPOGENÒ. Ask your doctor what to do if you miss a dose of EPOGENÒ.

Always keep a spare syringe and needle on hand.

When you receive your EPOGENÒ from the dialysis center, doctor's office or pharmacy, always check t o see that:

1. The name EPOGENÒ appears on the carton and vial label.

2. You will be able to use EPOGENÒ before the expiration date stamped on the package.

The EPOGENÒ solution in the vial should always be clear and colorless. Do not use EPOGENÒ if the contents ofthe vial appear discolored or cloudy, or if the vial appears to contain lumps, flakes, or particles. In addition, if the vial has been shaken vigorously, the solution may appear to be frothy and should not be used. Care should be taken not to shake the EPOGENÒ vial before use.

Always use the correct syringe.

Your doctor has instructed you on how to give yourself the correct dosage of EPOGENÒ. This dosage will usually be measured in Units per milliliter or ccs. It is important to use a syringe that is marked in tenths of milliliters (for example, 0.2 mL or cc). Using the wrong syringe can lead to a mistake in your dose, and you may receive too much or too little EPOGENÒ. Too little EPOGENÒ may not be effective in increasing the number of red blood cells. Too much EPOGENÒ may lead to serious problems because too many red blood cells are being produced (a hemoglobin or hematocrit that is too high).

Only use disposable syringes and needles. Use the syringe once and dispose of it as instructed by your doctor.

Single Use Vials-S

If you have been prescribed EPOGENÒ vials for single use, your vial will have a capital "S" with a number next to it identifying the concentration of EPOGENÒ in the vial, printed in a colored dot on the front left side of the label (for example, "S2" identifies a single use vial with 2000 Units/mL). Single use means the vial cannot be used more than once, and any unused portion of the vial should be discarded as directed by your doctor.

Multidose Use Vials-M

If you have been prescribed EPOGENÒ Multidose vials, your vial will have a capital "M" with a number under it identifying the concentration of EPOGENÒ in the vial, printed in a colored dot on the front left side of the label (for example, "M10" identifies a Multidose vial with 10,000 Units/mL). Multidose EPOGENÒ can be used to inject multiple doses as prescribed by your doctor, and may be stored between doses in the refrigerator (but not the freezer) for up to 21 days. Follow your doctor's or dialysis centers instructions on what to do with the used vials.

IMPORTANT: TO HELP AVOID CONTAMINATION AND POSSIBLE INFECTION, FOLLOW THESE INSTRUCTIONS EXACTLY.

Preparing the dose

1. Remove the vial of EPOGENÒ from the refrigerator and allow it to reach room temperature. Do not leave the vial in direct sunlight. Each EPOGENÒ vial is designed to be used only once, unless you are using a Multidose vial. Do not shake EPOGENÒ. Assemble the other supplies you will need for your injection (vial; syringe; alcohol antiseptic wipes and a container for disposing the needle).

2. Check the date on the EPOGENÒ vial to be sure that the drug has not expired.

3. Wash your hands thoroughly with soap and water before preparing the medication.

4. Wipe off the venous port of the hemodialysis tubing with an antiseptic swab or cleanse the skin with an antiseptic swab where the injection is to be made. Be careful not to touch the area that has been wiped with the antiseptic.

5. Flip off the protective cap but do not remove the gray rubber stopper. Wipe the top of the gray rubber stopper with an antiseptic swab.

6. Using a syringe and needle that has been ordered by your doctor, carefully remove the needle cover. Then, draw air into the syringe by pulling back on the plunger. The amount of air should be equal to your EPOGENÒ dose/volume.

7. With the vial on a flat work surface, put the needle through the gray rubber stopper of the EPOGENÒ vial.

8. Push the plunger in to discharge air into the vial. The air injected into the vial will allow EPOGENÒ to be easily withdrawn into the syringe.

9. Turn the vial and syringe upside down in one hand. Be sure the tip of the needle is in the EPOGENÒ solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw the correct dose of EPOGENÒ into the syringe.

10. Check for air bubbles. A small amount of air is harmless, but too large an air bubble will reduce the EPOGENÒ dose. To remove air bubbles, gently tap the syringe with your fingers to move the air bubbles to the top of the syringe, then use the plunger to push the solution and the air back into the vial. Keeping the tip of the needle in the EPOGENÒ solution, refill the syringe with your correct dose of EPOGENÒ.

11. Double-check that you have the correct dose in the syringe. Remove the needle from the vial. Do not lay the syringe down or allow the needle to touch anything.

Injecting the dose

EPOGENÒ can be injected into your body using two different ways as described below. Make sure you discuss with your doctor and understand which way is best for you. In patients on hemodialysis, the IV route is recommended.

1. SUBCUTANEOUS Route: EPOGENÒ can be injected directly into a layer of fat under your skin. This is called a subcutaneous injection. When receiving subcutaneous injections, always change the site for each injection as directed by your doctor. You may wish to record and track the site where you have injected. Do not inject EPOGENÒ into an area that is tender, red, bruised, hard, or has scars or stretch marks. Recommended sites for injection are presented in the figure below, including the outer area of the upper arm, the abdomen (except for the two-inch area around the navel), the front of the middle thighs, and the outer area of the buttocks.

2. INTRAVENOUS Route: EPOGENÒ can be injected in your vein through a special access port put in by your doctor. This type of EPOGENÒ injection is called an intravenous injection. This route is usually for hemodialysis patients. If you have a dialysis vascular access, to make sure it is working, continue to check your access as your doctor or nurse has shown you. Be sure to let your healthcare provider know right away if you are having any problems, or if you have any questions.

Using the subcutaneous route:

1. With one hand, hold the area surrounding the cleaned skin either by spreading it or by pinching up a large area. Do not touch the cleansed area.

2. Double-check that the correct amount of EPOGENÒ is in the syringe.

3. Hold the syringe with the other hand, as you would a pencil, insert the needle into the skin at a 45-degree angle. Let go of the skin and pull the plunger back slightly. If blood comes into the syringe, do not inject EPOGENÒ, as the needle has entered a blood vessel; withdraw the syringe, clean a new area, follow steps 1 and 2 and inject at a different site. If blood does not enter the syringe, inject the EPOGENÒ by pushing the plunger all the way down.

4. Pull the needle straight out of the skin and immediately press the antiseptic swab over the injection site for several seconds.

Using the intravenous injection route (hemodialysis patients):

1. Insert the needle ofthe syringe into the clean venous port and inject the EPOGENÒ.

How should I dispose of syringes and needles?

Remove the syringe and dispose of the whole unit WITHOUT RECAPPING THE NEEDLE. Use the disposable syringe only once. Dispose of syringes and needles as directed by your doctor, by following these simple steps:

- Place all used needles and syringes in a labeled hard-plastic container with a screw-on-cap, or a labeled metal container with a plastic lid, such as a coffee can properly labeled as to content. If a metal container is used, cut a small hole in the plastic lid and tape the lid to the metal container. If a hard-plastic container is used, always screw the cap on tightly after each use. When the container is full, tape around the cap or lid, and dispose of according to your doctor's instructions.

- Do not use glass or clear plastic containers, or any container that will be recycled or returned to a store.

- ALWAYS store the container out of the reach of children.

- Please check with your doctor, nurse, or pharmacist for other suggestions. There may be special state and local laws that they will discuss with you. DO NOT THROW THE CONTAINER IN YOUR HOUSEHOLD TRASH.

How should I store EPOGENÒ?

EPOGENÒ should be stored in the refrigerator, but NEVER in the freezer. Do not use a vial of EPOGENÒ that has been frozen. Do not leave the vial in direct sunlight. If you have any questions about EPOGENÒ that has been exposed to temperature extremes, be sure to check with your doctor. When traveling, transport EPOGENÒ in its original carton in an insulated container with a coolant such as blue ice. To avoid freezing, make sure the EPOGENÒ vial does not touch the coolant. Once you arrive, your EPOGENÒ should be placed in a refrigerator as soon as possible.

General information about EPOGENÒ

Doctors can prescribe medicines for conditions that are not in this leaflet. Use EPOGENÒ only for what your doctor prescribed. Do not give it to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet gives the most important patient information about EPOGENÒ. For more information talk to your doctor or healthcare provider (www.epogen.com, 1-800-77AMGEN)

Active Ingredients: Epoetin alfa

Inactive Ingredients: Albumin (human), sodium citrate, sodium chloride, and citric acid in water for injection

CLINICAL PHARMACOLOGY

Chronic Renal Failure Patients

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.2 In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 Units/mL and increase up to 100- to 1000-fold during hypoxia or anemia.2 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.3,4

Chronic renal failure is the clinical situation in which there is a progressive and usually irreversible decline in kidney function. Such patients may manifest the sequelae of renal dysfunction, including anemia, but do not necessarily require regular dialysis. Patients with end-stage renal disease (ESRD) are those patients with CRF who require regular dialysis or kidney transplantation for survival.

EPOGENÒ has been shown to stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require regular dialysis.4-13 The first evidence of a response to the three times weekly (TIW) administration of EPOGENÒ 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.4,5 Because of the length of time required for erythropoiesis several days 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 suggested target range (30% to 36%), that level can be sustained by EPOGENÒ therapy in the absence of iron deficiency and concurrent illnesses.

The rate of hematocrit increase varies between patients and is dependent upon the dose of EPOGENÒ, within a therapeutic range of approximately 50 to 300 Units/kg TIW.4 A greater biologic response is not observed at doses exceeding 300 Units/kg TIW.6 Other factors affecting the rate and extent of response include availability of iron stores, the baseline hematocrit, and the presence of concurrent medical problems.

Zidovudine-treated HIV-infected Patients

Responsiveness to EPOGENÒ in HIV-infected patients is dependent upon the endogenous serum erythropoietin level prior to treatment. Patients with endogenous serum erythropoietin levels £ 500 mUnits/mL, and who are receiving a dose of zidovudine £4200 mg/week, may respond to EPOGENÒ therapy. Patients with endogenous serum erythropoietin levels > 500 mUnits/mL do not appear to respond to EPOGENÒ therapy. In a series of four clinical trials involving 255 patients, 60% to 80% of HIV-infected patients treated with zidovudine had endogenous serum erythropoietin levels £500 mUnits/mL.

Response to EPOGENÒ in zidovudine-treated HIV-infected patients is manifested by reduced transfusion requirements and increased hematocrit.

Cancer Patients on Chemotherapy

A series of clinical trials enrolled 131 anemic cancer patients who received EPOGENÒ TIW and who were receiving cyclic cisplatin- or non cisplatin-containing chemotherapy. Endogenous baseline serum erythropoietin levels varied among patients in these trials with approximately 75% (n = 83/110) having endogenous serum erythropoietin levels £132 mUnits/mL, and approximately 4% (n = 4/110) of patients having endogenous serum erythropoietin levels > 500 mUnits/mL. In general, patients with lower baseline serum erythropoietin levels responded more vigorously to EPOGENÒ than patients with higher baseline erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would be unlikely to respond to EPOGENÒ therapy, treatment of patients with grossly elevated serum erythropoietin levels (eg, > 200 mUnits/mL) is not recommended.

Pharmacokinetics

In adult and pediatric patients with CRF, the elimination half-life of plasma erythropoietin after intravenously administered EPOGENÒ ranges from 4 to 13 hours.14-16 The half-life is approximately 20% longer in CRF patients than that in healthy subjects. After SC administration, peak plasma levels are achieved within 5 to 24 hours. The half-life is similar between adult patients with serum creatinine level greater than 3 and not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in EPOGENÒ half-life among adult patients above or below 65 years of age.

The pharmacokinetic profile of EPOGENÒ in children and adolescents appears to be similar to that of adults. Limited data are available in neonates.17 A study of 7 preterm very low birth weight neonates and 10 healthy adults given IV erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.42

The pharmacokinetics of EPOGENÒ have not been studied in HIV-infected patients.

A pharmacokinetic study comparing 150 Units/kg SC TIW to 40,000 Units SC weekly dosing regimen was conducted for 4 weeks in healthy subjects (n = 12) and for 6 weeks in anemic cancer patients (n = 32) receiving cyclic chemotherapy. There was no accumulation of serum erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3- to 7-fold), longer Tmax (2- to 3-fold), higher AUC0-168h (2- to 3-fold) of erythropoietin and lower clearance (50%) than the 150 Units/kg TIW regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg TIW dosing, the values of Tmax and clearance are similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/h/kg) between Week 1 when patients were receiving chemotherapy (n = 14) and Week 3 when patients were not receiving chemotherapy (n = 4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower clearance (9.2 ± 4.7 mL/h/kg) during Week 1 when patients were receiving chemotherapy (n = 18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/h/kg) during Week 3 when patients were not receiving chemotherapy (n = 7).

The bioequivalence between the 10,000 Units/mL citrate-buffered Epoetin alfa formulation and the 40,000 Units/mL phosphate-buffered Epoetin alfa formulation has been demonstrated after SC administration of single 750 Units/kg doses to healthy subjects.

REFERENCES

2. Graber SE, Krantz SB. Erythropoietin and the Control of Red Cell Production. Ann Rev Med. 1978;29:51-66.
3. Eschbach JW, Adamson JW. Anemia of End-Stage Renal Disease (ESRD). Kidney Intl. 1985;28: 1-5.
4. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin. NEJM. 1987;316:73-78.
5. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human Erythropoietin in Anemic Patients with End-Stage Renal Disease. Ann Intem Med. 1989;111:992-1000.
6. Eschbach JW, Egrie JC, Downing MR, et al. The Use of Recombinant Human Erythropoietin (r-HuEPO): Effect in End-Stage Renal Disease (ESRD). In: Friedman, Beyer, DeSanto, Giordano, eds. Prevention of Chronic Uremia. Philadelphia, PA: Field and Wood Inc; 1989:148-155.
7. Egrie JC, Eschbach JW, McGuire T, Adamson JW. Pharmacokinetics of Recombinant Human Erythropoietin (r-HuEPO) Administered to Hemodialysis (HD) Patients. Kidney Intl. 1988;33:262.
8. Evans RW, Rader B, Manninen DL, et al. The Quality of Life of Hemodialysis Recipients Treated with Recombinant Human Erythropoietin. JAMA. 1990;263:825-830.
9. Paganini E, Garcia J, Ellis P, et al. Clinical Sequelae of Correction of Anemia with Recombinant Human Erythropoietin (r-HuEPO); Urea Kinetics, Dialyzer Function and Reuse. Am J Kid Ois. 1988;11:16.
10. Delano BG, Lundin AP, Golansky R, et al. Dialyzer Urea and Creatinine Clearances Not Significantly Changed in r-HuEPO Treated Maintenance Hemodialysis (MD) Patients. Kidney Intl. 1988;33:219.
11. Stivelman J, Van Wyck D, Ogden D. Use of Recombinant Erythropoietin (r-HuEPO) with High Flux Dialysis (HFD) Does Not Worsen Azotemia or Shorten Access Survival. Kidney Intl. 1988;33:239.
12. Lim VS, DeGowin RL, Zavala D, et al. Recombinant Human Erythropoietin Treatment in Pre-Dialysis Patients: A Double-Blind Placebo Controlled TriaL. Ann Int Med. 1989;110:108-114.
13. Stone WJ, Graber SE, Krantz SB, et al. Treatment of the Anemia of Pre-Dialysis Patients with Recombinant Human Erythropoietin: A Randomized, Placebo-Controlled TriaL. Am J Med Sci.1988;296: 171-179.
14. Braun A, Ding R, Seidel C, Fies T, Kurtz A, Scharer K. Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure. Pediatr Nephrol. 1993;7:61-64.
15. Geva P, Sherwood JB. Pharmacokinetics of recombinant human erythropoietin (rHuEPO) in pediatric patients on chronic cycling peritoneal dialysis (CCPD). Blood. 1991 ;78 (Suppl 1):91 a.
16. Jabs K, Grant JR, Harmon W, et al. Pharmacokinetics of Epoetin alfa (rHuEPO) in pediatric hemodialysis (HD) patients. JAm Soc Nephrol. 1991 ;2:380.
17. Kling PJ, Widness JA, Guillery EN, Veng-Pedersen P, Peters C, DeAlarcon PA. Pharmacokinetics and pharmacodynamics of erythropoietin during therapy in an infant with renal failure. J Pediatr. 1992;121 :822-825.
42. Widness JA, Veng-Pedersen P, Peters C, Pereira LM, Schmidt RL, Lowe SL. Erythropoietin Pharmacokinetics in Premature Infants: Developmental, Nonlinearity, and Treatment Effects. J Appl Physiol. 1996;80 (1):140-148.

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 EPOGENÒ (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 EPOGENÒ, 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

EPOGENÒ is generally well-tolerated. The adverse events reported are frequent sequelae of CRF and are not necessarily attributable to EPOGENÒ therapy. In double-blind, placebo-controlled studies involving over 300 patients with CRF, the events reported in greater than 5% of patients treated with EPOGENÒ during the blinded phase were:

Percent of Patients Reporting Event
Event
Patients Treated With
EPOGENÒ
(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 %
Ml
0.4 %
1.1 %
Death
0 %
1.7 %

In the US EPOGENÒ 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 EPOGENÒ 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, EPOGENÒ 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 EPOGENÒ. 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 EPOGENÒ (150 Units/kg TIW) relative to the placebo group.

Seizures: There have been 47 seizures in 1010 patients on dialysis treated with EPOGENÒ 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.37-39

Thrombotic Events: In clinical trials where the maintenance hematocrit was 35 ± 3% on EPOGENÒ, 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 EPOGENÒ, there have been rare reports of serious or unusual thrombo-embolic 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 EPOGENÒ 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 EPOGENÒ therapy. If an anaphylactoid reaction occurs, EPOGENÒ should be immediately discontinued and appropriate therapy initiated.

Zidovudine-treated HIV-infected Patients

Adverse events reported in clinical trials with EPOGENÒ in zidovudine-treated HIV-infected patients were consistent with the progression of HIV infection. In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse events with an incidence of ³ 10% in either patients treated with EPOGENÒ or placebo-treated patients were:

Percent of Patients Reporting Event
Event
Patients Treated With
EPOGENÒ
(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, EPOGENÒ was not associated with significant increases in opportunistic infections or mortality.25 In 71 patients from this group treated with EPOGENÒ at 150 Units/kg TIW, serum p24 antigen levels did not appear to increase.27 Preliminary data showed no enhancement of HIV replication in infected cell lines in vitro.25

Peripheral white blood cell and platelet counts are unchanged following EPOGENÒ 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 EPOGENÒ and one was treated with placebo (EPOGENÒ 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 EPOGENÒ 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 EPOGENÒ in zidovudine-treated HIV-infected patients, 10 patients have experienced seizures.25 In general, these seizures appear to be related to underlying pathology such as meningitis or cerebral neoplasms, not EPOGENÒ therapy.

Cancer Patients on Chemotherapy

Adverse experiences reported in clinical trials with EPOGENÒ administered TIW in cancer patients were consistent with the underlying disease state. 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 EPOGENÒ or placebo-treated patients were as indicated below:

Percent of Patients Reporting Event
Event
PatientsTreated With
EPOGENÒ
(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 EPOGENÒ and placebo-treated patients were noted, the overall safety profile of EPOGENÒ 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 EPOGENÒ) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of EPOGENÒ 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 EPOGENÒ 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 ³ 10% are shown in the following table:

Percent of Patients Reporting Event
Event
Patients
Treated
With
EPOGENÒ
300 U/kg
(n = 112)a
Patients
Treated
With
EPOGENÒ
100 U/kg
(n = 101)a
Placebo-
treated
Patients
n (= 103)a
Patients
Treated
With
EPOGENÒ
600 U/kg
(n = 73)b
Patients
Treated
With
EPOGENÒ
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 EPOGENÒ or placebo for 15 days
b Study including patients undergoing orthopedic surgery treated with EPOGENÒ 600 Units/kg weekly x 4 or 300 Units/kg daily x 15
c Determined by clinical symptoms

Thrombotic/Nascular 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.18,20,28 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. However, the incidence of DVTs was within the range of that reported in the literature for orthopedic surgery patients.

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 EPOGENÒ group (5%) and no subjects in the 300 Units/kg daily group had a thrombotic vascular event during the study period.19

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. A causative role of Epoetin alfa cannot be excluded (see WARNINGS).

DRUG INTERACTIONS

No evidence of interaction of EPOGENÒ with other drugs was observed in the course of clinical trials.

REFERENCES

18. deAndrade JR and Jove M. Baseline Hemoglobin as a Predictor of Risk of Transfusion and Response to Epoetin alfa in Orthoperdic Surgery Patients. Am. J. of Orthoped. 1996;25 (8):533-542.
19. Goldberg MA and McCutchen JW. A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin alfa in Patients Undergoing Major Orthopedic Surgery. Am. J. of Orthoped. 1996;25 (8):544-552.
20. Faris PM and Ritter MA. The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopedic Operation. J. Bone and Joint surgery. 1996;78-A:62-72.
25. Ortho Biologics, Inc., data on file.
27. Fischl M, Galpin JE, Levine JD, et al. Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine. NEJM. 1990;322: 1488-1493.
28. Laupacis A. Effectiveness of Perioperative Recombinant Human Eyrthropoietin in Elective Hip Replacement. Lancet. 1993;341: 1228-1232.
37. Raskin NH, Fishman RA. Neurologic Disorders in Renal Failure (First of Two Parts). NEJM. 1976;294: 143-148.
38. Raskin NH and Fishman RA. Neurologic Disorders in Renal Failure (Second of Two Parts). NEJM. 1976;294:204-210.
39. Messing RO, Simon RP. Seizures as a Manifestation of Systemic Disease. Neurologic Clinics. 1986;4:563-584.

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

Thrombotic Events and Increased Mortality

A randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure) was conducted in which patients were assigned to EPOGENÒ treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%.40 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 these studies 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%.

Increased mortality was also observed in a randomized placebo-controlled study of EPOGENÒ in adult patients who did not have CRF who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to EPOGENÒ versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period ot study drug administration and all four deaths were associated with thrombotic events. While the extent of the population affected is unknown, in patients at risk for thrombosis, the anticipated benefits of EPOGENÒ treatment should be weighed against the potential for increased risks associated with therapy.

In a randomized, prospective trial conducted with another Epoetin alfa product, in 939 women with metastatic carcinoma of the breast who were receiving chemotherapy, patients were assigned to receive either Epoetin alfa or placebo for up to a year, in a weekly schedule, with the primary goal of showing improved survival and improved quality of life in the Epoetin alfa treatment arm.25 This study utilized a treatment strategy designed to maintain hemoglobin levels of 12 to 14 g/dL (hematocrit 36 to 42%). Increased mortality in the first 4 months after randomization was observed among 469 patients who received the erythropoietin product [41 deaths (8.7% mortality)] compared to 470 patients who received placebo [16 deaths (3.4% mortality)]. In the first four months of the study, the incidence of fatal thrombotic vascular events (1.1% vs 0.2%) and death attributed to disease progression (6.0% vs 2.8%) were both higher in the group randomized to receive Epoetin alfa as compared to placebo.

Based on Kaplan-Meier estimates, the proportion of subjects surviving at 12 months after randomization was lower in the Epoetin alfa group than in the placebo group (70% vs 76%), p = 0.012, log rank. However, due to Insufficient monitoring and data collection, reliable comparisons cannot be made concerning the effect of Epoetin alfa on overall time to disease progression, progression-free survival, and overall survival.

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 EPOGENÒ. This has been reported predominantly in patients with CRF receiving EPOGENÒ by subcutaneous administration. Any patient who develops a sudden loss of response to EPOGENÒ, 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 EPOGENÒ and other erythropoietic proteins. Contact Amgen (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies. EPOGENÒ 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)

EPOGENÒ 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 EPOGENÒ; blood pressure should be controlled adequately before initiation of therapy. Up to 80% of patients with CRF have a history of hypertension.29 Although there does not appear to be any direct pressor effects of EPOGENÒ, blood pressure may rise during EPOGENÒ 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 EPOGENÒ.

Special care should be taken to closely monitor and aggressively control blood pressure in patients treated with EPOGENÒ. 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 EPOGENÒ. A clinically significant decrease in hemoglobin may not be observed for several weeks.

It is recommended that the dose of EPOGENÒ 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 hemoglobin should be managed carefully, not to exceed 12 g/dL (see THROMBOTIC EVENTS).

Seizures: Seizures have occurred in patients with CRF participating in EPOGENÒ 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 EPOGENÒ be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period.

Thrombotic Events: During hemodialysis, patients treated with EPOGENÒ 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 EPOGENÒ 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 EPOGENÒ 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, EPOGENÒ therapy has not been linked to exacerbation of hypertension, seizures, and thrombotic events in HIV-infected patients.

PRECAUTIONS

The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with EPOGENÒ therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information regarding allergic reactions).

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

In some female patients, menses have resumed following EPOGENÒ therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

Hematology

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

In preclinical studies in dogs and rats, but not in monkeys, EPOGENÒ therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with EPOGENÒ for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with EPOGENÒ.

Hemoglobin in CRF patients should be measured twice a week; zidovudine-treated HIV-infected and cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.

Lack or Loss of Response

If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated:

1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION).

2. Underlying infectious, inflammatory, or malignant processes.

3. Occult blood loss.

4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders).

5. Vitamin deficiencies: Folic acid or vitamin B12.

6. Hemolysis.

7. Aluminum intoxication.

8. Osteitis fibrosa cystica.

9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia).

Iron Evaluation

During EPOGENÒ therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL.

Prior to and during EPOGENÒ therapy, the patient's iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by EPOGENÒ. All surgery patients being treated with EPOGEN should receive adequate iron supplementation throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenic potential of EPOGENÒ has not been evaluated. EPOGENÒ does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with EPOGENÒ, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C

EPOGENÒ has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. EPOGENÒ should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. EPOGENÒ has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers

Postnatal observations of the live offspring (F1 generation) of female rats treated with EPOGENÒ during gestation and lactation revealed no effect of EPOGENÒ at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no EPOGENÒ-related effects on the F2 generation fetuses.

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

Pediatric Use

See WARNINGS: Pediatrics.

Pediatric Patients on Dialysis: EPOGENÒ is indicated in infants (1 month to 2 years), children (2 years to 12 years), and adolescents (12 years to 16 years) for the treatment of anemia associated with CRF requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established (see CLINICAL EXPERIENCE: CHRONIC RENAL FAILURE, PEDIATRIC PATIENTS ON DIALYSIS). The safety data from these studies show that there is no increased risk to pediatric CRF patients on dialysis when compared to the safety profile of EPOGENÒ in adult CRF patients (see ADVERSE REACTIONS and WARNINGS). Published literature30-33 provides supportive evidence of the safety and effectiveness of EPOGENÒ in pediatric CRF patients on dialysis.

Pediatric Patients Not Requiring Dialysis: Published literature33.34 has reported the use of EPOGENÒ in 133 pediatric patients with anemia associated with CRF not requiring dialysis, ages 3 months to 20 years, treated with 50 to 250 Units/kg SC or IV, QW to TIW. Dose-dependent increases in hemoglobin and hematocrit were observed with reductions in transfusion requirements.

Pediatric HIV-infected Patients: Published literature 35,36 has reported the use of EPOGENÒ in 20 zidovudine-treated anemic HIV-infected pediatric patients ages 8 months to 17 years, treated with 50 to 400 Units/kg SC or IV, 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts, and decreases in or elimination of blood transfusions were observed.

Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of EPOGENÒ were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients).

Geriatric Use

Among 1051 patients enrolled in the 5 clinical trials of EPOGENÒ for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received EPOGENÒ and 306 received placebo. Of the 745 patients who received EPOGENÒ, 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for EPOGENÒ in geriatric and younger patients within the 4 trials using the TIW schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.

Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received EPOGENÒ and 125 received placebo. Of the 757 patients who received EPOGENÒ, 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hematocrit (See DOSAGE AND ADMINISTRATION).

Insufficient numbers of patients age 65 or older were enrolled in clinical studies of EPOGENÒ for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.

Chronic Renal Failure Patients

Patients with CRF Not Requiring Dialysis

Blood pressure and hemoglobin should be monitored no less frequently than for 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.

Hematology

Sufficient time should be allowed to determine a patient's responsiveness to a dosage of EPOGENÒ before adjusting the dose. Because of the time required for erythropoiesis and the red cell half-life, an interval of 2 to 6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontinuation) and a significant change in hemoglobin.

In order to avoid reaching the suggested target hemoglobin too rapidly, or exceeding the suggested target range (hemoglobin of 10 g/dL to 12 g/dL), the guidelines for dose and frequency of dose adjustments (see DOSAGE AND ADMINISTRATION) should be followed.

For patients who respond to EPOGENÒ with a rapid increase in hemoglobin (eg, more than 1 g/dL in any 2-week period), the dose of EPOGENÒ should be reduced because of the possible association of excessive rate of rise of hemoglobin with an exacerbation of hypertension.

The elevated bleeding time characteristic of CRF decreases toward normal after correction of anemia in adult patients treated with EPOGENÒ. Reduction of bleeding time also occurs after correction of anemia by transfusion.

Laboratory Monitoring

The hemoglobin should be determined twice a week until it has stabilized in the suggested target range and the maintenance dose has been established. After any dose adjustment, the hemoglobin should also be determined twice weekly for at least 2 to 6 weeks until it has been determined that the hemoglobin has stabilized in response to the dose change. The hemoglobin 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 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 adult patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. In some adult patients with CRF not on dialysis treated with EPOGENÒ, 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.

Diet

As the hemoglobin 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. In US studies in patients on dialysis, hyperkalemia has occurred at an annualized rate of approximately 0.11 episodes per patient-year of EPOGENÒ therapy, often in association with poor compliance to medication, diet, and/or dialysis.

Dialysis Management

Therapy with EPOGENÒ results in an increase in hematocrit and a decrease in plasma volume which could affect dialysis efficiency. In studies to date, the resulting increase in hematocrit did not appear to adversely affect dialyzer function9,10 or the efficiency of high flux hemodialysis.11 During hemodialysis, patients treated with EPOGENÒ may require increased anticoagulation with heparin to prevent clotting of the artificial kidney.

Patients who are marginally dialyzed may require adjustments in their dialysis prescription. As with all patients on dialysis, the serum chemistry values (including BUN, creatinine, phosphorus, and potassium) in patients treated with EPOGENÒ should be monitored regularly to assure the adequacy of the dialysis prescription.

Information for Patients

In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer EPOGENÒ at home, instruction as to the proper dosage and administration should be provided. Patients should be referred to the full "Information for Patients" insert and that it is not a disclosure of all possible effects. Patients should be informed of the possible side effects of EPOGENÒ and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, 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 should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container.

Renal Function

In adult 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 progression of renal dysfunction over periods of greater than 1 year have not been completed. In shorter term trials in adult patients with CRF not on dialysis, changes in creatinine and creatinine clearance were not significantly different in patients treated with EPOGENÒ compared with placebo-treated patients. Analysis of the slope of 1/serum creatinine versus time plots in these patients indicates no significant change in the slope after the initiation of EPOGENÒ therapy.

Zidovudine-treated HIV-infected Patients

Hypertension

Exacerbation of hypertension has not been observed in zidovudine-treated HIV-infected patients treated with EPOGENÒ. However, EPOGENÒ should be withheld in these patients if pre-existing hypertension is uncontrolled, and should not be started until blood pressure is controlled. In double-blind studies, a single seizure has been experienced by a patient treated with EPOGENÒ.25

Cancer Patients on Chemotherapy

Hypertension

Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with EPOGENÒ. Nevertheless, blood pressure in patients treated with EPOGENÒ should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.

Seizures

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with EPOGENÒ TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with EPOGENÒ TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with EPOGENÒ also had underlying CNS pathology which may have been related to seizure activity.

In a placebo-controlled, double-blind trial utilizing weekly dosing with EPOGENÒ, 1.2% (n = 2/168) of safety-evaluable patients treated with EPOGENÒ and 1 % (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly EPOGENÒ occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology.

Thrombotic Events

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with EPOGENÒ TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (See WARNINGS; Thrombotic Events and Increased Mortality).

In a placebo-controlled, double-blind trial utilizing weekly dosing with EPOGENÒ, 6.0% (n = 10/168) of safety-evaluable patients treated with EPOGENÒ and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study.

The safety and efficacy of EPOGENÒ were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of EPOGENÒ on the incidence of thrombotic events could not be performed. In the EPOGENÒ arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.

Tumor Growth Factor Potential

EPOGENÒ is a growth factor that primarily stimulates red cell production. Erythropoietin receptors are also found to be present on the surface of some malignant cell lines and tumor biopsy specimens. However, it is not known if these receptors are functional. A randomized, placebo-controlled trial was conducted in 224 chemotherapy-naive, non-anemic patients with small cell lung cancer receiving cisplatin-based combination chemotherapy, to investigate whether the concurrent use of EPOGENÒ stimulated tumor growth as assessed by impact on overall response rate. Patients were randomized to receive EPOGENÒ 150 Units/kg or placebo subcutaneously TIW during chemotherapy. The overall response rates, after 3 cycles of treatment, were 72% and 67%, in the EPOGENÒ and placebo arms, respectively. Complete response rates (17% vs. 14%) and median overall survival (10.5 mos vs. 10.4 mos) were similar in the EPOGENÒ and placebo arms.25

Two additional studies explored effect on survival and/or progression of administrations of other exogenous erythropoietin with higher hemoglobin targets.

In a randomized, placebo-controlled study using another Epoetin alfa product, conducted in 939 women with metastatic breast cancer, study drug dosing was titrated to attempt to maintain hemoglobin levels between 12 and 14 g/dL. At four months, death attributed to disease progression was higher (6% vs 3%) in women receiving Epoetin alfa. Overall mortality was significantly higher at 12 months in the Epoetin alfa arm (See WARNINGS; Thrombotic Events and Increased Mortality).

In a randomized, placebo-controlled study using Epoetin beta, conducted in 351 patients with head and neck cancer, study drug was administered with the aim of achieving a hemoglobin level of 14 g/dL in women and 15 g/dL in men. Locoregional progression-free survival was significantly shorter (median PFS: 406 days Epoetin beta vs 745 days placebo, p = 0.04) in patients receiving Epoetin beta.41

There is Insufficient information to establish whether use of Epoetin products, including EPOGENÒ, have an adverse effect on time to tumor progression or progression-free survival.

These trials permitted or required dosing to achieve hemoglobin of greater than 12 g/dL. Until further information is available, the recommended target hemoglobin should not exceed 12 g/dL in men or women.

Surgery Patients

Thrombotic/Nascular Events

In perioperative clinical trials with orthopedic patients, the overall incidence of thrombotic/vascular events was similar in Epoetin alfa and placebo-treated patients who had a pretreatment hemoglobin of > 10 g/dL to £ 13 g/dL. In patients with a hemoglobin of > 13 g/dL treated with 300 Units/kg of Epoetin alfa, the possibility that EPOGENÒ treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded.18-20,28

In one study in which Epoetin alfa was administered in the perioperative period to patients undergoing coronary artery bypass graft surgery, there were 7 deaths in the group treated with Epoetin alfa (n = 126) and no deaths in the placebo-treated group (n = 56). Among the 7 deaths in the patients treated with Epoetin alfa, 4 were at the time of therapy (between study day 2 and 8). The 4 deaths at the time of therapy (3%) were associated with thrombotic/vascular events. A causative role of Epoetin alfa cannot be excluded (see WARNINGS).

Hypertension

Blood pressure may rise in the perioperative period in patients being treated with EPOGENÒ. Therefore, blood pressure should be monitored carefully.

REFERENCES

9. Paganini E, Garcia J, Ellis P, et al. Clinical Sequelae of Correction of Anemia with Recombinant Human Erythropoietin (r-HuEPO); Urea Kinetics, Dialyzer Function and Reuse. Am J Kid Ois. 1988;11:16.
10. Delano BG, Lundin AP, Golansky R, et al. Dialyzer Urea and Creatinine Clearances Not Significantly Changed in r-HuEPO Treated Maintenance Hemodialysis (MD) Patients. Kidney Intl. 1988;33:219.
11. Stivelman J, Van Wyck D, Ogden D. Use of Recombinant Erythropoietin (r-HuEPO) with High Flux Dialysis (HFD) Does Not Worsen Azotemia or Shorten Access Survival. Kidney Intl. 1988;33:239.
18. deAndrade JR and Jove M. Baseline Hemoglobin as a Predictor of Risk of Transfusion and Response to Epoetin alfa in Orthoperdic Surgery Patients. Am. J. of Orthoped. 1996;25 (8):533-542.
19. Goldberg MA and McCutchen JW. A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin alfa in Patients Undergoing Major Orthopedic Surgery. Am. J. of Orthoped. 1996;25 (8):544-552.
20. Faris PM and Ritter MA. The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopedic Operation. J. Bone and Joint surgery. 1996;78-A:62-72.
25. Ortho Biologics, Inc., data on file.
28. Laupacis A. Effectiveness of Perioperative Recombinant Human Eyrthropoietin in Elective Hip Replacement. Lancet. 1993;341: 1228-1232.
29. Kerr DN. Chronic Renal Failure. In: Beeson PB, McDermott W, Wyngaarden JB, eds. Cecil Textbook of Medicine. Philadelphia, PA: W.B. Saunders; 1979:1351-1367.
30. Campos A, Garin EH. Therapy of renal anemia in children and adolescents with recombinant human erythropoietin (rHuEPO). Clin Pediatr (Phila). 1992;31 :94-99.
31. Montini G, Zacchello G, Baraldi E, et al. Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodialysis. J Pediatr. 1990; 117:556-560.
32. Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J, Scigalla P. One year's experience with recombinant erythropoietin in children undergoing continuous ambulatory or cycling peritoneal. dialysis. Pediatr Nephrol. 1990;4:498-500.
33. Muller-Wiefel DE, Scigalla P. Specific problems of renal anemia in childhood. Contrib Nephrol. 1988;66:71-84.
34. Scharer K, Klare B, Dressel P, Gretz N. Treatment of renal anemia by subcutaneous erythropoietin in children with preterminal chronic renal failure. Acta Paediatr. 1993;82:953-958.
35. Mueller BU, Jacobsen RN, Jarosinski P, et al. Erythropoietin for zidovudine-associated anemia in children with HIV infection. Pediatr AIDS and HIV Infect: Fetus to Adolesc. 1994;5:169-173.
36. Zuccotti GV, Plebani A, Biasucci G, et al. Granulocyte-colony stimulating factor and erythropoietin therapy in children with human immunodeficiency virus infection. J Int Med Res. 1996;24:115-121.
40. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. NEJM. 1998;339:584-90.
41. Henke, M, Laszig, R, Rube, C., et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. The Lancet. 2003; 362:1255-1260.

OVERDOSE

The maximum amount of EPOGENÒ that can be safely administered in single or multiple doses has not been determined. Doses of up to 1500 Units/kg TIW for 3 to 4 weeks have been administered to adults without any direct toxic effects of EPOGENÒ itself.6 Therapy with EPOGENÒ can result in polycythemia if the hemoglobin is not carefully monitored and the dose appropriately adjusted. If the suggested target range is exceeded, EPOGENÒ may be temporarily withheld until the hemoglobin returns to the suggested target range; EPOGENÒ therapy may then be resumed using a lower dose (see DOSAGE AND ADMINISTRATION). If polycythemia is of concern, phlebotomy may be indicated to decrease the hemoglobin.

CONTRAINDICATIONS

EPOGENÒ is contraindicated in patients with:

1. Uncontrolled hypertension.

2. Known hypersensitivity to mammalian cell-derived products.

3. Known hypersensitivity to Albumin (Human).

REFERENCES

6. Eschbach JW, Egrie JC, Downing MR, et al. The Use of Recombinant Human Erythropoietin (r-HuEPO): Effect in End-Stage Renal Disease (ESRD). In: Friedman, Beyer, DeSanto, Giordano, eds. Prevention of Chronic Uremia. Philadelphia, PA: Field and Wood Inc; 1989:148-155.