Epogen

[Epoetin alfa]

Zidovudine-treated HIV-infected Patients

EPOGEN (r) 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. [Amgen]).

In the subgroup of patients (89/ 125 EPOGEN (r) and 88/ 130 placebo) with prestudy endogenous serum erythropoietin levels 500 mUnits/ mL, EPOGEN (r) 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 EPOGEN (r) versus 18% of placebo-treated patients were transfusion-independent during the second and third months of therapy. EPOGEN (r) therapy also resulted in significant increases in hematocrit in comparison to placebo.

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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 EPOGEN (r) (n = 51) compared to placebo treated patients (n = 54) whose mean weekly zidovudine dose was 4200 mg/ week. Approximately 17% of the patients with endogenous serum erythropoietin levels 500 mUnits/ mL receiving EPOGEN (r) 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, EPOGEN (r) therapy did not reduce transfusion requirements or increase hematocrit, compared to the corresponding responses in placebo-treated patients.

In a 6 month open-label EPOGEN (r) study, patients responded with decreased transfusion requirements and sustained increases in hematocrit and hemoglobin with doses of EPOGEN (r) up to 300 Units/ kg TIW. Responsiveness to EPOGEN (r) therapy may be blunted by intercurrent infectious/ inflammatory episodes and by an increase in zidovudine dosage. Consequently, the dose of EPOGEN (r) must be titrated based on these factors to maintain the desired erythropoietic response.

Cancer Patients on Chemotherapy

EPOGEN (r) has been studied in a series of placebo-controlled, double-blind trials in a total of 131 anemic cancer patients. Within this group, 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 EPOGEN (r) 150 Units/ kg or placebo subcutaneously TIW for 12 weeks.

EPOGEN (r) therapy was associated with a significantly (p < 0.008) greater hemat-ocrit response than in the corresponding placebo-treated patients (see table).
Hematocrit (%): Mean Change From
Baseline to Final Value*
Study EPOGEN (r) Placebo
Chemotherapy 7.6 1.3
Cisplatin 6.9 0.6
*Significantly higher in EPOGEN (r) patients than in placebo patients (p < 0.008)

In the two types of chemotherapy studies (utilizing an EPOGEN (r) dose of 150 Units/ kg TIW), the mean number of units of blood transfused per patient after the first month of therapy was significantly (p < 0.02) lower in patients treated with EPOGEN (r) (0.71 units in months 2, 3) than in corresponding placebo-treated patients (1.84 units in months 2, 3).

Moreover, the proportion of patients transfused during months 2 and 3 of therapy combined was significantly (p < 0.03) lower in the patients treated with EPOGEN (r) than in the correspond-ing placebo-treated patients (22% vs 43%). Comparable intensity of chemotherapy in the EPOGEN (r) and placebo groups in the chemotherapy trials was suggested by a similar area under the neutrophil time curve in patients treated with EPOGEN (r) and placebo-treated patients as well as by a similar proportion of patients in groups treated with EPOGEN (r) and place-bo-treated groups whose absolute neutrophil counts fell below 1000 cells/ µL.

Available evidence suggests that patients with lymphoid and solid cancers respond equivalently to EPOGEN (r) therapy, and that patients with or without tumor infiltration of the bone marrow respond equivalently to EPOGEN (r) therapy.

Surgery Patients

EPOGEN (r) 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 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 EPOGEN (r) , 100 Units/ kg EPOGEN (r) or placebo by SC injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

All patients received oral iron and a low-dose post-operative warfarin regimen. Treatment with EPOGEN (r) 300 Units/ kg significantly (p = 0.024) reduced the risk of allogeneic transfusion in patients with a pretreatment hemoglobin of > 10 to 13 g/ dL; 5/ 31 (16%) of EPOGEN (r) 300 Units/ kg, 6/ 26 (23%) of EPOGEN (r) 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 EPOGEN (r) (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 EPOGEN (r) is useful in this hemoglobin strata.

In the > 10 to 13 g/ dL pretreatment stratum, the mean number of units transfused per EPOGEN (r) -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 EPOGEN (r) .

EPOGEN (r) was also studied in an openlabel, parallel-group trial enrolling 145 subjects with a pretreatment hemoglobin level of 10 to 13 g/ dL who were scheduled for major orthopedic hip or knee surgery and who were not participat-ing in an autologous program. 19 Subjects were randomly assigned to receive one of two SC dosing regimens of EPOGEN (r) (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. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 x 10 6 /mm 3 ) compared to the daily group (0.17 x 10 6 /mm 3 ). 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). 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 EPOGEN (r) 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 EPOGEN (r) should be reduced as the hematocrit approaches 36% or increases by more than 4 points in any 2-week period. The dosage of EPOGEN (r) must be individualized to maintain the hematocrit within the suggested target range. At the physician's discretion, the suggested target hematocrit range may be expanded to achieve maximal patient benefit.

EPOGEN (r) may be given either as an IV or SC injection. In patients on hemodialysis, EPOGEN (r) usually has been administered as an IV bolus TIW. While the administration of EPOGEN (r) is independent of the dialysis procedure, EPOGEN (r) may be administered into the venous line at the end of the dialysis procedure to obviate the need for additional venous access. In adult patients with CRF not on dialysis, EPOGEN (r) may be given either as an IV or SC injection.

Patients who have been judged competent by their physicians to self-administer EPOGEN (r) 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 50 to 100 Units/ kg TIW; IV or SC
Pediatric Patients 50 Units/ kg TIW; IV or SC
Reduce Dose When:
1. Hct. approaches 36% or,
2. Hct. increases > 4 points in any 2-week period
Increase Dose If: Hct. does not increase by 5 to 6 points after 8 weeks of therapy, and hct. is below suggested target range

Maintenance Dose

Individually titrate
Suggested Target
Hct. Range: 30% to 36%
During therapy, hematological parameters should be monitored regularly (see LABORATORY MONITORING).

Pretherapy Iron Evaluation:

Prior to and during EPOGEN (r) 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 trans-ferrin saturation to levels that will adequately support erythropoiesis stimulated by EPOGEN (r) .

Dose Adjustment

Following EPOGEN (r) therapy, a period of time is required for erythroid progenitors to mature and be released into circulation resulting in an eventual increase in hematocrit. Additionally, red blood cell survival time
affects hematocrit and may vary due to uremia. As a result, the time required to elicit a clinically significant change in hematocrit (increase or decrease) following any dose adjustment may be 2 to 6 weeks. Dose adjustment should not be made more frequently than once a month, unless clinically indicated. After any dose adjustment, the hematocrit should be determined twice weekly for at least 2 to 6 weeks (see LABORATORY MONITORING).

°If the hematocrit is increasing and approaching 36%, the dose should be
reduced to maintain the suggested target hematocrit range. If the reduced
dose does not stop the rise in hematocrit, and it exceeds 36%, doses should be temporarily withheld until the hematocrit begins to decrease, at which point therapy should be reinitiated at a lower dose.

°At any time, if the hematocrit increases by more than 4 points in a 2-week
period, the dose should be immediately decreased. After the dose reduction, the hematocrit should be monitored twice weekly for 2 to 6 weeks, and further dose adjustments should be made as outlined in
MAINTENANCE DOSE.

°If a hematocrit increase of 5 to 6 points is not achieved after an 8-week period and iron stores are adequate (see LACK OR LOSS OF RESPONSE), the dose of EPOGEN (r) may be incrementally increased. Further increases may be made at 4 to 6 week intervals until the desired response is attained.

Maintenance Dose

The maintenance dose must be individualized for each patient on dialysis. In the US phase 3 multicenter trial in patients on hemodialysis, the median maintenance dose was 75 Units/ kg TIW, with a range from 12.5 to 525 Units/ kg TIW. Almost 10% of the patients required a dose of 25 Units/ kg, or less, and approximately 10% of the patients required more than 200 Units/ kg TIW to maintain their hematocrit in the suggested target range. In pediatric hemodialysis and peritoneal dialysis patients, the median maintenance dose was 167 Units/ kg/ week (49 to 447 Units/ kg per week) and 76 Units/ kg per week (24 to 323 Units/ kg/ week) administered in divided doses (TIW or BIW), respectively to achieve the target range of 30% to 36%.

If the hematocrit 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 EPOGEN (r) 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 hematocrit to a dose increase can be 2 to 6 weeks.

Hematocrit 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. EPOGEN (r) 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

Over 95% of patients with CRF responded with clinically significant increases in hematocrit, and virtually all patients were transfusion-independent within approximately 2 months of initiation of EPOGEN (r) therapy. If a patient fails to respond or maintain a response, other etiologies should be considered and evaluated as clinically indicated (see PRECAUTIONS for discus-sion of lack or loss of response).

Zidovudine-treated HIV-infected Patients

Prior to beginning EPOGEN (r) , it is recommended that the endogenous serum erythropoietin level be determined (prior to transfusion). Available evidence suggests that patients receiving zidovudine with endogenous serum erythropoietin levels > 500 mUnits/ mL are unlikely to respond to therapy with EPOGEN (r) .

Starting Dose

For adult patients with serum erythropoietin levels 500 mUnits/ mL who are receiving a dose of zidovudine 4200 mg/ week, the recommended
starting dose of EPOGEN (r) 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 hematocrit should be monitored weekly. If the response is not satisfactory in terms of reduc-ing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose of EPOGEN (r) can be increased by 50 to 100 Units/ kg TIW. Response should be evaluated every 4 to 8 weeks thereafter and the dose adjusted accord-ingly by 50 to 100 Units/ kg increments TIW. If patients have not responded satisfactorily to an EPOGEN (r) dose of 300 Units/ kg TIW, it is unlikely that they will respond to higher doses of EPOGEN (r) .

Maintenance Dose

After attainment of the desired response (ie, reduced transfu-sion requirements or increased hematocrit), the dose of EPOGEN (r) should be titrated to maintain the response based on factors such as variations in zidovudine dose and the presence of intercurrent infectious or inflammatory episodes. If the hematocrit exceeds 40%, the dose should be discontinued until the hematocrit drops to 36%. The dose should be reduced by 25% when treatment is resumed and then titrated to maintain the desired hematocrit.

Cancer Patients on Chemotherapy

Baseline endogenous serum erythropoietin levels varied among patients in these trials with approximately 75% (n = 83/ 110) having endogenous serum erythro-poietin 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 vigor-ously to EPOGEN (r) than patients with higher erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would be unlikely to respond to EPOGEN (r) therapy, treatment of patients with grossly elevated serum erythropoietin levels (eg, > 200 mUnits/ mL) is not recommended. The hematocrit should be monitored on a weekly basis in patients receiving EPOGEN (r) therapy until hematocrit becomes stable.

Starting Dose

The recommended starting dose of EPOGEN (r) for adults is 150 Units/ kg SC TIW. For pediatric patients, see PRECAUTIONS: PEDIATRIC USE.

Dose Adjustment:

If the response is not satisfactory in terms of reducing transfu-sion requirements or increasing hematocrit after 8 weeks of therapy, the dose of EPOGEN (r) can be increased up to 300 Units/ kg TIW. If patients have not responded satisfactorily to an EPOGEN (r) dose of 300 Units/ kg TIW, it is unlike-ly that they will respond to higher doses of EPOGEN (r) . If the hematocrit exceeds 40%, the dose of EPOGEN (r) should be withheld until the hematocrit falls to 36%. The dose of EPOGEN (r) should be reduced by 25% when treatment is resumed and titrated to maintain the desired hematocrit. If the initial dose of EPOGEN (r) includes a very rapid hematocrit response (eg, an increase of more than 4 percentage points in any 2-week period), the dose of EPOGEN (r) should be reduced.

Surgery Patients

Prior to initiating treatment with EPOGEN (r) a hemoglobin should be obtained to establish that it is > 10 to 13 g/ dL. 18 The recommended dose of EPOGEN (r) is 300 Units/ kg/ day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery. An alternate dose schedule is 600 Units/ kg EPOGEN (r) subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery. All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with EPOGEN (r) and should continue throughout the course of therapy.

PREPARATION AND ADMINISTRATION OF EPOGEN (r)

1. Do not shake. It is not necessary to shake EPOGEN (r) . 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 EPOGEN (r) , 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 EPOGEN (r) 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 discom-fort. Admixing is not necessary when using the multidose vials of EPOGEN (r) containing benzyl alcohol.

HOW SUPPLIED

EPOGEN (r) , 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.
REFERENCES

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2. Graber SE, Krantz SB. Erythropoietin and the Control of Red Cell
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5. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human
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10. Delano BG, Lundin AP, Golansky R, et al. Dialyzer Urea and Creatinine
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27. Fischl M, Galpin JE, Levine JD, et al. Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine. NEJM. 1990; 322: 1488-1493.

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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.

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42. 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.

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Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
(c)1989 -2002 Amgen Inc. All rights reserved.
3106809 Issue Date: 10/ 18/ 2002 P30380B
EPOGEN (r) (Epoetin alfa) 8 EPOGEN (r) (Epoetin alfa) 9 EPOGEN (r) (Epoetin alfa) 10 EPOGEN (r) (Epoetin alfa) 11 EPOGEN (r) (Epoetin alfa) 12 EPOGEN (r) (Epoetin alfa) 13 EPOGEN (r) (Epoetin alfa) 14 2

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