Procrit

[Epoetin alfa]

Among those patients who required transfusions at baseline, 43% of patients treated with PROCRIT versus 18% of placebo-treated patients were transfusion-independent during the second and third months of therapy. PROCRIT 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 PROCRIT (N= 51) compared to placebo-treated patients (N= 54) whose mean weekly zidovudine dose was 4,200 mg/ week.

Approximately 17% of the patients with endogenous serum erythropoietin levels 500 mUnits/ mL receiving PROCRIT in doses from 100-200 Units/ kg three times weekly (T. I. W.) achieved a hematocrit of 38% without administration of transfusions or a significant reduction in zidovudine dose. In the subgroup of patients whose prestudy endogenous serum erythropoietin levels were > 500 mUnits/ mL, PROCRIT therapy did not reduce transfusion requirements or increase hematocrit, compared to the corresponding responses in placebo-treated patients. In a six month open-label PROCRIT study, patients responded with decreased transfusion requirements and sustained increases in hematocrit and hemoglobin with doses of PROCRIT up to 300 Units/ kg (T. I. W.).

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

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Patients were randomized to PROCRIT 150 Units/ kg or placebo subcutaneously (T. I. W.) for 12 weeks. PROCRIT therapy was associated with a significantly (p< 0.008) greater hematocrit response than in the corresponding placebo-treated patients (see TABLE). 25 HEMATOCRIT (%): MEAN CHANGE FROM BASELINE TO FINAL VALUE a STUDY PROCRIT PLACEBO Chemotherapy 7.6 1. 3 Cisplatin 6.9 0. 6 a Significantly higher in PROCRIT patients than in placebo patients (p < 0.008) In the two types of chemotherapy studies [utilizing a PROCRIT dose of 150 Units/ kg (T. I. W.)] 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 PROCRIT (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 PROCRIT than in the corresponding placebo-treated patients (22% versus 43%).

Comparable intensity of chemotherapy in the PROCRIT and placebo groups in the chemotherapy trials was suggested by a similar area under the neutrophil time curve in patients treated with PROCRIT and placebo-treated patients as well as by a similar proportion of patients in groups treated with PROCRIT and placebo-treated groups whose absolute neutrophil counts fell below 1,000 cells/ µL. Available evidence suggests that patients with lymphoid and solid cancers respond equivalently to PROCRIT therapy, and that patients with or without tumor infiltration of the bone marrow respond equivalently to PROCRIT therapy.

Surgery Patients

PROCRIT 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, 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 U/ kg PROCRIT, 100 U/ kg PROCRIT or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for four days after surgery 18 .

All patients received oral iron and a low dose postoperative warfarin regimen. 18 Treatment with PROCRIT 300 U/ 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 PROCRIT 300 U/ kg, 6/ 26 (23%) of PROCRIT 100 U/ kg and 13/ 29 (45%) of placebo-treated patients were transfused. 18 There was no signif-icant difference in the number of patients transfused between PROCRIT (9% 300 U/ kg, 6% 100 U/ 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 PROCRIT is useful in this hemoglobin strata. In the >10 to 13 g/ dL pretreatment stratum, the mean number of units transfused per PROCRIT-treated patient (0.45 units blood for 300 U/ kg, 0.42 units blood for 100 U/ 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 PROCRIT-treated patients. 18 PROCRIT was also studied in an open-label, 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 participating in an autologous program. 19 Subjects were randomly assigned to receive one of two subcutaneous dosing regimens of PROCRIT (600 U/ kg once weekly for three weeks prior to surgery and on the day of surgery or 300 U/ kg once daily for 10 days prior to surgery, on the day of surgery and for four days after surgery).

All subjects received oral iron and appropriate pharmacologic anticoagulation therapy. From pretreatment to presurgery, the mean increase in hemoglobin in 600 U/ kg weekly group (1.44 g/ dL) was greater than observed in the 300 U/ kg daily group. 19 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 U/ kg weekly group and 14/ 71 (20%) in the 300 U/ kg daily group]. 19 The mean number of units transfused per subject was approximately 0.3 units in both treatment groups.

PREPARATION AND ADMINISTRATION OF PROCRIT

1. DO NOT SHAKE. It is not necessary to shake PROCRIT. 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 PROCRIT, 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 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 subcuta-neous administration, preservative-free PROCRIT 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 subcutaneous injection site discomfort. Admixing is not necessary when using the multidose vials of PROCRIT containing benzyl alcohol.

HOW SUPPLIED

PROCRIT, containing Epoetin alfa, is available in vials containing color coded labels.

1 mL Single-Dose, Preservative-Free Solution Each dosage form is supplied in the following packages: Cartons containing six (6) single-dose vials: 2,000 Units/ mL (NDC 59676-302-01) (Purple) 3,000 Units/ mL (NDC 59676-303-01) (Magenta) 4,000 Units/ mL (NDC 59676-304-01) (Green) 10,000 Units/ mL (NDC 59676-310-01) (Red) Cartons containing four (4) single-dose vials: 40,000 Units/ mL (NDC 59676-340-01) (Orange) Trays containing twenty-five (25) single-dose vials: 2,000 Units/ mL (NDC 59676-302-02) (Purple) 3,000 Units/ mL (NDC 59676-303-02) (Magenta) 4,000 Units/ mL (NDC 59676-304-02) (Green) 10,000 Units/ mL (NDC 59676-310-02) (Red) 2 mL Multidose, Preserved Solution Cartons containing six (6) multidose vials: 10,000 Units/ mL (NDC 59676-312-01) (Blue) 1 mL Multidose, Preserved Solution Cartons containing six (6) multidose vials: 20,000 Units/ mL (NDC 59676-320-01) (Lime) STORAGE Store at 2° to 8° C (36° to 46° F). Do not freeze or shake.

REFERENCES:

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

2. Graber SE and Krantz SB, (1978). "Erythropoietin and the Control of Red Cell Production." Ann. Rev. Med. 29: 51-66.

3. Eschbach JW and Adamson JW, (1985). "Anemia of End-Stage Renal Disease (ESRD)." Kidney Intl. 28: 1-5.

4. Eschbach JW, Egrie JC, Downing MR, Browne JK, and Adamson JW, (1987). "Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin." NEJM 316: 73-78.

5. Eschbach JW, Abdulhadi MH, Browne JK, et al., (1989). "Recombinant Human Erythropoietin in Anemic Patients with End-Stage Renal Disease." Ann. Intern. Med. 111: 992-1000.

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

7. Egrie JC, Eschbach JW, McGuire T, and Adamson JW, (1988). "Pharmacokinetics of Recombinant Human Erythropoietin (r-HuEPO) Administered to Hemodialysis (HD) Patients." Kidney Intl. 33: 262.

8. Evans RW, Rader B, Manninen DL, et al., (1990). "The Quality of Life of Hemodialysis Recipients Treated with Recombinant Human Erythropoietin." JAMA 263: 825-830.

9. Paganini E, Garcia J, Ellis P, Bodnar D, and Magnussen M, (1988). "Clinical Sequelae of Correction of Anemia with Recombinant Human Erythropoietin (r-HuEPO); Urea Kinetics, Dialyzer Function and Reuse." Am. J. Kid. Dis. 11: 16.

10. Delano BG, Lundin AP, Golansky R, Quinn RM, Rao TKS, and Friedman EA, (1988). "Dialyzer Urea and Creatinine Clearances Not Significantly Changed in r-HuEPO Treated Maintenance Hemodialysis (MD) Patients." Kidney Intl. 33: 219.

11. Stivelman J, Van Wyck D, and Ogden D, (1988). "Use of Recombinant Erythropoietin (r-HuEPO) with High Flux Dialysis (HFD) Does Not Worsen Azotemia or Shorten Access Survival." Kidney Intl. 33: 239.

12. Lim VS, DeGowin RL, Zavala D, Kirchner PT, Abels R, Perry P, and Fangman J, (1989). "Recombinant Human Erythropoietin Treatment in Pre-Dialysis Patients: A Double-Blind Placebo-Controlled Trial." Ann. Int. Med. 110: 108-114.

13. Stone WJ, Graber SE, Krantz SB, et al., (1988). "Treatment of the Anemia of Pre-Dialysis Patients with Recombinant Human Erythropoietin: A Randomized, Placebo-Controlled Trial." Am. J. Med. Sci. 296: 171-179.

14. Braun A, Ding R, Seidel C, et al., (1993). "Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to chil-dren with chronic renal failure." Pediatr Nephrol. 7: 61-64.

15. Geva P and Sherwood JB, (1991). "Pharmacokinetics of recombinant human erythropoietin (rHuEPO) in pediatric patients on chronic cycling peritoneal dialysis (CCPD)." Blood. 78 (Suppl 1): 91a.

16. Jabs K, Grant JR, Harmon W, et al., (1991). "Pharmacokinetics of Epoetin alfa (rHuEPO) in pediatric hemodialysis (HD) patients." J Am Soc Nephrol. 2: 380.

17. Kling PJ, Widness JA, Guillery EN, et al., (1992). "Pharmacokinetics and pharmaco-dynamics of erythropoietin during therapy in an infant with renal failure." J Pediatr. 121: 822-825.

18. de Andrade JR and Jove M, (1996). "Baseline Hemoglobin as a Predictor of Risk of Transfusion and Response to Epoetin alfa in Orthopedic Surgery Patients." Am. J. of Orthoped. 25( 8): 533-542.

19. Goldberg MA and McCutchen JW, (1996). "A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin alfa in Patients Undergoing Major Orthopedic Surgery." Am. J. of Orthoped. 25( 8): 544-552.

20. Faris PM and Ritter MA, (1996). "The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopaedic Operation." J. Bone and Joint Surg. 78-A: 62-72.

21. Lundin AP, Akerman MJH, Chesler RM, Delano BG, Goldberg N, Stein RA, and Friedman EA, (1991). "Exercise in Hemodialysis Patients after Treatment with Recombinant Human Erythropoietin" Nephron. 58: 315-319.

22. Data on file, Amgen Inc.

23. Eschbach JW, Kelly MR, Galey NR, Abels RI and Adamson JU (1989). "Treatment of the Anemia of Progressive Renal Failure with Recombinant Human Erythropoietin," NEJM 321: 158-163.

24. The US Recombinant Human Erythropoietin Predialysis Study Group (1991). "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. 18( 1): 50-59.

25. Data on file, Ortho Biologics, Inc.

26. Danna RP, Rudnick SA, and Abels RI, (1990). "Erythropoietin Therapy for the Anemia Associated with AIDS and AIDS Therapy and Cancer." Erythropoietin in Clinical ApplicationsÑ An International Perspective, (MB Garnick, ed.), Marcel Dekker, New York, NY, pp. 301-324.

27. Fischl M, Galpin JE, Levine JD, et al., (1990). "Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine." NEJM 322: 1488-1493.

28. Laupacis A, (1993). "Effectiveness of Perioperative Recombinant Human Erythropoietin in Elective Hip Replacement." Lancet 341: 1228-1232.

29. Kerr DN, (1979). "Chronic Renal Failure," Cecil Textbook of Medicine, (Beeson PB, McDermott W, Wyngaarden JB, eds.), W. B. Saunders, Philadelphia, PA, pp 1351-1367.

30. Campos A and Garin EH. (1992). "Therapy of renal anemia in children and adolescents with recombinant human erythropoietin (rHuEPO)." Clin Pediatr (Phila). 31: 94-99.

31. Montini G, Zacchello G, Baraldi E, et al., (1990). "Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodialysis." J Pediatr. 117: 556-560.

32. Offner G, Hoyer PF, Latta K, et al., (1990). "One year's experience with recombinant erythropoietin in children undergoing continuous ambulatory or cycling peritoneal dialysis." Pediatr Nephrol. 4: 498-500.

33. Muller-Wiefel DE and Scigalla P, (1988). "Specific problems of renal anemia in childhood." Contrib Nephrol. 66: 71-84.

34. Scharer K, Klare B, Dressel P, and Gretz N, (1993) "Treatment of renal anemia by subcutaneous erythropoietin in children with preterminal chronic renal failure." Acta Paediatr. 82: 953-958.

35. Mueller BU, Jacobsen RN, Jarosinski P, et al., (1994). "Erythropoietin for zidovudine-associated anemia in children with HIV infection." Pediatr AIDS and HIV Infect: Fetus to Adolesc. 5: 169-173.

36. Zuccotti GV, Plebani A, Biasucci G, et al., (1996). "Granulocyte-colony stimulating factor and erythropoietin therapy in children with human immunodeficiency virus infec-tion." J Int Med Res. 24: 115-121.

37. Beck MN and Beck D, (1995). "Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer." Med Pediatr Oncol. 25: 17-21.

38. Bennetts G, Bertolone S, Bray G, et al., (1995). "Erythropoietin reduces volumes of red cell transfusions required in some subsets of children with acute lymphocytic leukemia." Blood. 86: 853a.

39. Raskin NH and Fishman RA, (1976). "Neurologic Disorders in Renal Failure (First of Two Parts)." NEJM 294: 143-148.

40. Raskin NH and Fishman RA, (1976). "Neurologic Disorders in Renal Failure (Second of Two Par ts)." NEJM 294: 204-210.

41. Messing RO and Simon RP,( 1986). "Seizures as a Manifestation of Systemic Disease." Neurologic Clinics 4: 563-584.

42. Besarab A, Bolton WK, Browne JK, et al., (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 339: 584-90.

43. Casadevall N, Nataf J, Viron B, et al., (2002). Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombi-nant erythropoietin. NEJM. 346: 469-475.

44. Gershon SK, Luksenberg H, Cote TR, Braun MM, (2002). Pure red-cell aplasia and recombinant erythropoietin. NEJM. 346: 1584-1586.

Manufactured by: Amgen Inc. U. S. Lic. # 1080 Thousand Oaks, California 91320-1799 Distributed by: Ortho Biotech Products, L. P. Raritan, New Jersey 08869-0670 Revised November 2002 (c) OBPLP 2000 638-29-980-1 3193604 7.

Carefully remove the needle cover. Put the needle through the gray rubber stopper of the PROCRIT vial.

8. Push the plunger in to discharge air into the vial. The air injected into the vial will allow PROCRIT 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 PROCRIT solution. Your other hand will be free to move the plunger. Draw back on the plunger slowly to draw the correct dose of PROCRIT into the syringe.

10. Check for air bubbles. The air is harmless, but too large an air bubble will reduce the PROCRIT dose. To remove air bubbles, gently tap the syringe 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. Then re-measure your correct dose of PROCRIT.

11. Double check your dose. Remove the needle from the vial. Do not lay the syringe down or allow the needle to touch anything.

INJECTING THE DOSE

Patients on home hemodialysis using the intravenous injection route:

1. Insert the needle of the syringe into the previously cleansed venous port and inject the PROCRIT.

2. Remove the syringe and dispose of the whole unit. 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 hard plastic container with a screw- on- cap, or a 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. Patients on home peritoneal dialysis or home hemodialysis using the sub- cutaneous route:
1. With one hand, stabilize the previously cleansed skin by spreading it or by pinch- ing up a large area with your free hand.

2. Hold the syringe with the other hand, as you would a pencil. Double check that the correct amount of PROCRIT is in the syringe. Insert the needle straight into the skin (90 degree angle). Pull the plunger back slightly. If blood comes into the syringe, do not inject PROCRIT, as the needle has entered a blood vessel; withdraw the syringe and inject at a different site. Inject the PROCRIT by pushing the plunger all the way down.

3. Hold an antiseptic swab near the needle and pull the needle straight out of the skin. Press the antiseptic swab over the injection site for several seconds.

4. 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 hard plastic container with a screw- on- cap, or a 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.

5. Always change the site for each injection as directed. Occasionally a problem may develop at the injection site. If you notice a lump, swelling, or bruising that doesn't go away, contact your doctor. You may wish to record the site just used so that you can keep track.

USAGE IN PREGNANCY

If you are pregnant or nursing a baby, consult your doctor before using PROCRIT. IMPORTANT NOTES Since you are a home dialysis patient and your doctor allows you to self- administer PROCRIT, please note the following:

1. Always follow the instructions of your doctor concerning the dosage and administration of PROCRIT. Do not change the dose or instructions for administration of PROCRIT without consulting your doctor.

2. Your doctor will tell you what to do if you miss a dose of PROCRIT. Always keep a spare syringe and needle on hand.

3. Always consult your doctor if you notice anything unusual about your condition or your use of PROCRIT.

Manufactured by: Amgen Inc. U. S. Lic. # 1080 Thousand Oaks, California 91320-1799 Distributed by: Ortho Biotech Products, L. P. Raritan, New Jersey 08869-0670 (c) OBPLP 2000 Revised November 2002 PROCRIT (r) (Epoetin alfa) 6 PROCRIT (r) (Epoetin alfa) 7 PROCRIT (r) (Epoetin alfa) 8 PROCRIT (r) (Epoetin alfa) 9 PROCRIT (r) (Epoetin alfa)

DOSAGE AND ADMINISTRATION

Chronic Renal Failure Patients

Starting doses of PROCRIT over the range of 50-100 Units/ kg three times weekly (T. I. W.) for adult patients. The recommended starting dose for pediatric CRF patients on dialysis is 50 Units/ kg three times weekly (T. I. W.). The dose of PROCRIT should be reduced as the hematocrit approaches 36% or increases by more than 4 points in any 2-week period. The dosage of PROCRIT 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.

PROCRIT may be given either as an intravenous (IV) or subcutaneous (SC) injection. In patients on hemodialysis, PROCRIT usually has been administered as an IV bolus (T. I. W.). While the administration of PROCRIT is independent of the dialysis procedure, PROCRIT 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, PROCRIT may be given either as an IV or SC injection. Patients who have been judged competent by their physicians to self-administer PROCRIT 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 T. I. W.; IV or SC Pediatric Patients 50 Units/ kg T. I. W.; 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").

Pre-Therapy Iron Evaluation:

Prior to and during PROCRIT 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 PROCRIT.

Dose Adjustment:

Following PROCRIT 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 2-6 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 2-6 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 2-6 weeks, and further dose adjustments should be made as outlined in "Maintenance Dose."

° If a hematocrit increase of 5-6 points is not achieved after an 8-week period and iron stores are adequate (see "Lack or Loss of Response"), the dose of PROCRIT may be incrementally increased. Further increases may be made at 4-6 week intervals until the desired response is attained.

Maintenance Dose:

The maintenance dose must be individualized for each patient on dialysis. In the U. S. Phase III multicenter trial in patients on hemodialysis, the median maintenance dose was 75 Units/ kg (T. I. W.), with a range from 12.5 to 525 Units/ kg (T. I. W.). 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 (T. I. W.) 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 (T. I. W. or B. I. W.), 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 PROCRIT 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 2-6 weeks. Hematocrit should be measured twice weekly for 2-6 weeks following dose increases. In adult patients with CRF not on dialysis, the maintenance dose must also be individualized. PROCRIT doses of 75-150 Units/ kg per week have been shown to maintain hematocrits of 36-38% 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 two months of initiation of PROCRIT therapy. If a patient fails to respond or maintain a response, other etiologies should be considered and evaluated as clinically indicated. (See "PRECAUTIONS" section for discussion of lack or loss of response.)

Zidovudine-Treated HIV-Infected Patients

Prior to beginning PROCRIT, 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 PROCRIT.

Starting Dose:

For adult patients with serum erythropoietin levels 500 mUnits/ mL who are receiving a dose of zidovudine 4,200 mg/ week, the recommended starting dose of PROCRIT is 100 Units/ kg as an intravenous or subcutaneous injection three times weekly (T. I. W.) 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 reducing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose of PROCRIT can be increased by 50-100 Units/ kg (T. I. W.). Response should be evaluated every 4-8 weeks thereafter and the dose adjusted accordingly by 50-100 Units/ kg increments (T. I. W.). If patients have not responded satisfactorily to a PROCRIT dose of 300 Units/ kg (T. I. W.), it is unlikely that they will respond to higher doses of PROCRIT.

Maintenance Dose:

After attainment of the desired response (i. e., reduced transfusion requirements or increased hematocrit), the dose of PROCRIT 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 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 PROCRIT than patients with higher erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would be unlikely to respond to PROCRIT therapy, treatment of patients with grossly elevated serum erythropoietin levels (e. g., > 200 mUnits/ mL) is not recommended. The hematocrit should be monitored on a weekly basis in patients receiving PROCRIT therapy until hematocrit becomes stable.

Starting Dose:

The recommended starting dose of PROCRIT for adults is 150 Units/ kg subcutaneously (T. I. W.). For pediatric patients, see "PRECAUTIONS, Pediatric Use."

Dose Adjustment:

If the response is not satisfactory in terms of reducing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose of PROCRIT can be increased up to 300 Units/ kg (T. I. W.). If patients have not responded satisfactorily to a PROCRIT dose of 300 Units/ kg (T. I. W.), it is unlikely that they will respond to higher doses of PROCRIT. If the hematocrit exceeds 40%, the dose of PROCRIT should be withheld until the hematocrit falls to 36%. The dose of PROCRIT should be reduced by 25% when treatment is resumed and titrated to maintain the desired hematocrit. If the initial dose of PROCRIT includes a very rapid hematocrit response (e. g., an increase of more than 4 percentage points in any 2-week period), the dose of PROCRIT should be reduced. Surgery Patients Prior to initiating treatment with PROCRIT a hemoglobin should be obtained to establish that it is >10 to 13 g/ dL. 18 The recommended dose of PROCRIT is 300 U/ 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 U/ kg PROCRIT subcutaneously in once weekly doses (21, 14 and 7 days before surgery) plus a fourth dose on day of surgery. 19 All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with PROCRIT and should continue throughout the course of therapy.

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