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Leukine Indications, Dosage, Storage, Stability - Sargramostim

Leukine Indications, Dosage, Storage, Stability - Sargramostim

INDICATIONS

Use Following Induction Chemotherapy in Acute Myelogenous Leukemia

Leukine is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of Leukine have not been assessed in patients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells

Leukine is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells lead to more rapid engraftment, which result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of Leukine following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation

Leukine is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin's disease, Leukine has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to Leukine can be detected by complete blood count (CBC) with differential performed twice per week.

Use in Myeloid Reconstitution after Allogeneic Bone Marrow Transplantation

Leukine is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Leukine has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay

Leukine is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. Leukine has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score < 2 (See CLINICAL PHARMACOLOGY: CLINICAL EXPERIENCE). Hematologic response to Leukine can be detected by complete blood count (CBC) with differential performed twice per week.

DOSAGE AND ADMINISTRATION

Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia

The recommended dose is 250 mcg/m2/day administered intravenously over a 4 hour period starting approximately on day 11 or 4 days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts. If a second cycle of induction chemotherapy is necessary, Leukine should be administered approximately 4 days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. Leukine should be continued until an ANC >1500/mm3 for 3 consecutive days or a maximum of 42 days. Leukine should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3 or ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Leukine therapy. Leukine treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.

Mobilization of Peripheral Blood Progenitor Cells

The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved (see CLINICAL EXPERIENCE, Mobilization and Engraftment of PBPC). If WBC > 50,000 cells/mm3, the Leukine dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.

Post Peripheral Blood Progenitor Cell Transplantation

The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500/mm3 for 3 consecutive days is attained.

Myeloid Reconstitution after Autologous or Allogeneic Bone Marrow Transplantation

The recommended dose is 250 mcg/m2/day administered IV over a 2 hour period beginning 2 to 4 hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive Leukine until the post marrow infusion ANC is less than 500 cells/mm3. Leukine should be continued until an ANC >1500/mm3 for 3 consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Leukine should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Leukine therapy. Leukine treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.

Bone Marrow Transplantation Failure or Engraftment Delay

The recommended dose is 250 mcg/m2/day for 14 days as a 2 hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Leukine should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Leukine therapy. Leukine treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.

Preparation of Leukine

1. Leukine Liquid is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500mcg/mL) in a vial. Lyophilized Leukine is a sterile, white, preservative-free powder (250mcg) that requires reconstitution with1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP.

2. Leukine Liquid may be stored for up to 20 days at 2-8-C once the vial has been entered. Discard any remaining solution after 20 days.

3. Lyophilized Leukine (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below). The contents of vials reconstituted with different diluents should not be mixed together.

Sterile Water for Injection, USP (without preservative): Leukine vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution.

Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2-8-C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including Leukine Liquid and lyophilized Leukine reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS).

4. During reconstitution the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.

5. Leukine should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of Leukine is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of Leukine to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g. use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP).

6. An in-line membrane filter should NOT be used for intravenous infusion of Leukine.

7. Store Leukine Liquid and reconstituted lyophilized Leukine solutions under refrigeration at 2-8­C (36-46­F); DO NOT FREEZE.

8. In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing Leukine. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.

9. Aseptic technique should be employed in the preparation of all Leukine solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED

Leukine Liquid is available in vials containing 500 mcg/mL (2.8 x 10⁶ IU/mL) sargramostim. Lyophilized Leukine is available in vials containing 250 mcg (1.4 x 10⁶ IU/vial)  sargramostim. 

Each dosage form is supplied as follows: 

Carton of 5 vials of lyophilized Leukine 250 mcg (NDC 58406-002-33). 

Carton of 5 multiple-dose vials; each vial contains 1mL of preserved 500 mcg/mL Leukine Liquid (NDC 58406-050-30). 

STORAGE

The sterile, preserved, injectable solution; the sterile powder; the reconstituted solution; and the diluted solution for injection should be refrigerated at 2-8­C (36-46­F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.

REFERENCES

1. Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 1986; 67(2):257-267.

2. Park LS, Friend D, Gillis S, Urdal DL. Characterization of the cell surface receptor for human granulocyte/macrophage colony stimulating factor. J Exp Med 1986; 164:251-262.

3. Grabstein KH, Urdal DL, Tushinski RJ, et al. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factors. Science 1986; 232:506-508.

4. Reed SG, Nathan CF, Pihl DL, et al. Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. J Exp Med 1987; 166:1734-1746.

5. Data on File Immunex Corporation; Seattle, WA.

6. Rowe JM, Andersen JW, Mazza JJ et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86(2):457-462.

7. Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancy: Pooled results of a randomized, double-blind, placebo controlled trial. NEJM 1991; 324(25):1773-1778.

8. Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocyte-macrophage colony stimulating factor in autologous bone marrow transplantation for lymphoid malignancies. Blood 1988; 72(2):834-836.

9. Nemunaitis J, Singer JW, Buckner CD, et al. Long-term follow-up of patients who received recombinant human granulocyte-macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy. BMT 1991; 7:49-52.

10. Goris RJA, Boekhorst T.A. Nuytinck JKS, et al. Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109-1115.

11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.

12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118.

13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552. 

15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857.

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