ASCO/ASH GUIDELINES ON THE USE OF EPOETIN

1. ASCO/ASH GUIDELINESON THE USE OF EPOETIN Use of Epoetin in Patients With Cancer: Evidence-Based Clinical Practice Guidelines of the American Society of Clinical Oncology and the American Society of Hematology J. Douglas Rizzo et al. Journal of Clinical Oncology, Vol 20, Issue 19 (October 1), 2002: 4083-4107

2. Historical Background • Anemia secondary to diagnosis of cancer or resulting from its treatment is an important clinical problem. • Transfusion was the traditional – and only – means of therapy for symptomatic anemia, until the 1990s. • Newer chemotherapeutic agents and drug combinations have made anemia an even more clinically significant problem. • Growing concern about infection risks has led to decreased usage of RBC transfusions.

3. Anemia of Malignancy • Infiltration of marrow element by cancer cells directly – bone marrow involvement. • The effect of cancer therapy. • Anemia of chronic disorders – inhibitory effect of tumor necrosis factor.

4. 1. The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a hemoglobin concentration that has declined to a level 10 g/dL. RBC transfusion is also an option depending upon the severity of anemia or clinical circumstances.

5. 2. For patients with declining hemoglobin levels but less severe anemia (those with hemoglobin concentration < 12 g/dL, but who have never fallen below 10 g/dL), the decision of whether to use epoetin immediately or to wait until hemoglobin levels fall closer to 10 g/dL should be determined by clinical circumstances. RBC transfusion is also a therapeutic option when warranted by severe clinical conditions.

6. 3. The recommendations are based on evidence from trials in which epoetin was administered subcutaneously thrice weekly. The recommended starting dose is 150 U/kg thrice weekly for a minimum of 4 weeks, with consideration given for dose escalation to 300 U/kg thrice weekly for an additional 4 to 8 weeks in those who do not respond to the initial dose. Although supported by less strong evidence, an alternative weekly dosing regimen (40,000 U/wk), based on common clinical practice, can be considered. Dose escalation of weekly regimens should be under similar circumstances to thrice weekly regimens.

7. 4. Continuing epoetin treatment beyond 6 to 8 weeks in the absence of response (eg, < 1-2 g/dL rise in hemoglobin), assuming appropriate dose increase has been attempted in nonresponders, does not appear to be beneficial. Patients who do not respond should be investigated for underlying tumor progression or iron deficiency. As with other failed individual therapeutic trials, consideration should be given to discontinuing the medication.

8. 5. Hemoglobin levels can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dL. Insufficient evidence to date supports the "normalization" of hemoglobin levels to above 12 g/dL.

9. 6. Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation, or ferritin levels and instituting iron repletion when indicated may be valuable in limiting the need for epoetin, maximizing symptomatic improvement for patients, and determining the reason for failure to respond adequately to epoetin. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring.

10. 7. There is evidence from one well-designed, placebo-controlled, randomized trial that supports the use of epoetin in patients with anemia associated with low-risk myelodysplasia, but there are no published high-quality studies to support its use in anemic myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukemia patients in the absence of chemotherapy. Treatment with epoetin for myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined above.

11. 8. Physicians caring for patients with myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukemia are advised to begin treatment with chemotherapy and/or corticosteroids and observe the hematologic outcomes achieved solely through tumor reduction before considering epoetin. If a rise in hemoglobin is not observed after chemotherapy, epoetin should be used in accordance with the criteria outlined above for chemotherapy-associated anemia if clinically indicated. Blood transfusion is also a therapeutic option.

12. Summary [1] • The use of epoetin is recommended in patients with chemotherapy associated anemia with Hb level less than 10 g/dl. • The use of epoetin for patients with less severe anemia (Hb < 12 g/dl and Hb > 10 g/dl) should be determined by clinical circumstances. • Doses: S.C. epoetin thrice weekly (150 U/kg TIW) for minimum 4 weeks or alternatively – 40,000 U/week dosing regimen. • Dose escalation should be considered for those not responding to initial dose.

13. Summary [2] • In the absence of response, continuing epoetin beyond 6-8 weeks does not appear to be beneficial. • Epoetin should be titrated once the Hb concentration reaches 12 g/dl. • For anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.

14. Clarification • All Information included in this document has been compiled from scientific journals. • The approved indication for Eprex according to the Israeli Drug Registry is: Treatment of anemia in cancer patients on chemotherapy, treatment of severe anemia associated with chronic renal failure, treatment of anemia in Zidovudine-treated HIV-infected patients, autologus blood donation and reduction of allogenic blood transfusion in surgery patients. • Prior to any utilization of EPREX, one must look carefully at the product’s patient and physician leaflets, and to act according to their provisions. • The information concerning the utilization of EPREX 40,000 IU once weekly dosing is brought only as general information, and should not be deemed as a recommendation or support for the said utilization. It is hereby clarified that according to Israeli law, such utilization is allowed only according to the provisions of Reg. 29 of the Pharmacists Regulations (Medicinal Product), 1986.