Drugs Details

Drugs Info of Leukine
Drugs Details
  • Drugs Type  : FDA
  • Date : 12th Feb 2015 08:15 am
  • Brand Name : Leukine
  • Generic Name : sargramostim (Pronunciation: sar GRA moe stim)
Descriptions

LEUKINE® (sargramostim) is a recombinant human granulocyte macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. LEUKINE (sargramostim) is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500, 16,800 and 15,500 daltons. The amino acid sequence of LEUKINE (sargramostim) differs from the natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from the native protein. Sargramostim has been selected as the proper name for yeast derived rhu GM-CSF.

The liquid LEUKINE (sargramostim) presentation is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE (sargramostim) is a sterile, white, preservative free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP. Liquid LEUKINE (sargramostim) has a pH range of 6.7 - 7.7 and lyophilized LEUKINE (sargramostim) has a pH range of 7.1 - 7.7.

Liquid LEUKINE (sargramostim) and reconstituted lyophilized LEUKINE (sargramostim) are clear, colorless liquids suitable for subcutaneous injection (SC) or intravenous infusion (IV). Liquid LEUKINE contains 500 mcg (2.8 x 106 IU/mL) sargramostim and 1.1% benzyl alcohol in a 1 mL solution. The vial of lyophilized LEUKINE (sargramostim) contains 250 mcg (1.4 x 106 IU/vial) sargramostim. The liquid LEUKINE (sargramostim) vial and reconstituted lyophilized LEUKINE (sargramostim) vial also contain 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, as excipients. Biological potency is expressed in International Units (IU) as tested against the WHO First International Reference Standard. The specific activity of LEUKINE (sargramostim) is approximately 5.6 x 106 IU/mg.

What are the possible side effects of sargramostim (Leukine)?

Some people receiving a sargramostim injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, short of breath, or have a fast heartbeat, chest tightness, or trouble breathing during the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • high fever, chills, sore...

Read All Potential Side Effects and See Pictures of Leukine »

What are the precautions when taking sargramostim (Leukine)?

Before using sargramostim, tell your doctor or pharmacist if you are allergic to it; or to other medications made in a similar manner (man-made proteins using Saccharomyces cerevisiae); or if you have any other allergies. This product may contain inactive ingredients (such as benzyl alcohol), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: fluid retention, lung problems, heart problems (e.g., congestive heart failure-CHF, rhythm problems), liver disease, kidney disease, other blood disorders (e.g., myeloid cancers), current chemotherapy.

If you are scheduled to have radiation therapy, tell your doctor you are taking sargramostim....

Read All Potential Precautions of Leukine »

This monograph has been modified to include the generic and brand name in many instances.

Indications

Use Following Induction Chemotherapy in Acute Myelogenous Leukemia

LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) 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 can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE (sargramostim) following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation

LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation

LEUKINE (sargramostim) is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLAmatched related donors. LEUKINE (sargramostim) 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 (sargramostim) is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE (sargramostim) 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 ≤ two (see Clinical Experience). Hematologic response to LEUKINE (sargramostim) can be detected by complete blood count (CBC) with differential performed twice per week.

Dosage Administration

Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia

The recommended dose is 250mcg/m²/day administered intravenously over a 4 hour period starting approximately on day 11 or four 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 (sargramostim) should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with < 5% blasts. LEUKINE (sargramostim) should be continued until an ANC > 1500 cells/mm³ for 3 consecutive days or a maximum of 42 days. LEUKINE (sargramostim) 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 (sargramostim) therapy. LEUKINE (sargramostim) treatment should be interrupted or the dose reduced by half 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 (sargramostim) 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 cells/mm³ for three consecutive days is attained.

Myeloid Reconstitution After Autologous or Allogeneic Bone MarrowTransplantation

The recommended dose is 250mcg/m²/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive LEUKINE (sargramostim) until the post marrow infusion ANC is less than 500 cells/mm³. LEUKINE (sargramostim) should be continued until an ANC > 1500 cells/mm³ for three 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 (sargramostim) 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 (sargramostim) therapy. LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) therapy. LEUKINE (sargramostim) treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Preparation of LEUKINE (sargramostim)

  1. Liquid LEUKINE (sargramostim) is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE (sargramostim) is a sterile, white, preservative-free powder (250mcg) that requires reconstitution with 1mL SterileWater for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP.
  2. Liquid LEUKINE (sargramostim) 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 (sargramostim) (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): Lyophilized LEUKINE (sargramostim) 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 liquid LEUKINE (sargramostim) and lyophilized LEUKINE (sargramostim) reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS).
  4. During reconstitution of lyophilized LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) 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 (sargramostim) 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%SodiumChloride Injection, USP (e.g., use 1mL 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 (sargramostim) .
  7. Store liquid LEUKINE (sargramostim) and reconstituted lyophilized LEUKINE (sargramostim) solutions under refrigeration at 2-8°C (36-46°F); DO NOT FREEZE.
  8. In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing LEUKINE (sargramostim) . 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 (sargramostim) 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. If particulate matter is present or the solution is discolored, the vial should not be used.

How Supplied

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

Each dosage form is supplied as follows:

Lyophilized LEUKINE (sargramostim)

Carton of five vials of lyophilized LEUKINE (sargramostim) 250 mcg (NDC 50419-002-33)

Liquid LEUKINE (sargramostim)

Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE (sargramostim) (NDC 50419-050-14)

Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE (sargramostim) . (NDC 50419-050-30)

Storage

LEUKINE (sargramostim) should be refrigerated at 2-8°C (36-46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.

Manufactured by: Bayer HealthCare Pharmaceuticals, LLC., Seattle, WA 98101. Revised April 2008. FDA rev date: 03/05/91

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

Autologous and Allogeneic Bone Marrow Transplantation

LEUKINE (sargramostim) is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE (sargramostim) or placebo were as reported in Table 6.

Table 6: Percent of AuBMT Patients Reporting Events

Events by Body System LEUKINE
(n=79)
Placebo
(n=77)
Events by Body System LEUKINE
(n=79)
Placebo
(n=77)
Body, General Metabolic, Nutritional Disorder
Fever 95 96 Edema 34 35
Mucous membrane dis order 75 78 Peripheral edema 11 7
Asthenia 66 51 Respiratory System
Malaise 57 51 Dyspnea 28 31
Sepsis 11 14 Lung disorder 20 23
Digestive System Hemic and Lymphatic System
Nausea 90 96 Blood dyscrasia 25 27
Diarrhea 89 82 Cardiovascular System
Vomiting 85 90 Hemorrhage 23 30
Anorexia 54 58 Urogenital System
GI disorder 37 47 Urinary tract disorder 14 13
GI hemorrhage 27 33 Kidney function abnormal 8 10
Stomatitis 24 29 Nervous System
Liver damage 13 14 CNS disorder 11 16
Skin and Appendages      
Alopecia 73 74      
Rash 44 38      

No significant differences were observed between LEUKINE (sargramostim) and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE (sargramostim) has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE (sargramostim) and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV LEUKINE (sargramostim) or placebo were as reported in Table 7.

Table 7: Percent of Allogeneic BMT Patients Reporting Events

Events by Body System LEUKINE
( n =53)
Placebo
(n=56)
Events by Body System LEUKINE
(n=53)
Placebo
(n=56)
Body, General Metabolic /Nutritional Disorders
Fever 77 80 Bilirubinemia 30 27
Abdominal pain 38 23 Hyperglycemia 25 23
Headache 36 36 Peripheral edema 15 21
Chills 25 20 Increased creatinine 15 14
Pain 17 36 Hypomagnesemia 15 9
Asthenia 17 20 Increased SGPT 13 16
Chest pain 15 9 Edema 13 11
Back pain 9 18 Increased alk . phosphatase 8 14
Digestive System Respiratory System
Diarrhea 81 66 Pharyngitis 23 13
Nausea 70 66 Epsitaxis 17 16
Vomiting 70 57 Dyspnea 15 14
Stomatitis 62 63 Rhinitis 11 14
Anorexia 51 57 Hemic and Lymphatic System
Dyspepsia 17 20 Thrombocytopenia 19 34
Hematemesis 13 7 Leukopenia 17 29
Dysphagia 11 7 Petechia 6 11
GI hemorrhage 11 5 Agranulo cytosis 6 11
Constipation 8 11 Urogenital System
Skin and Appendages Hematuria 9 21
Rash 70 73 Nervous System
Alopecia 45 45 Paresthesia 11 13
Pruritis 23 13 Insomnia 11 9
Musculo -skeletal System Anxiety 11 2
Bone pain 21 5 Laboratory Abnormalities*
Arthralgia 11 4 High glucose 41 49
Special Senses Low albumin 27 36
Eye hemorrhage 11 0 High BUN 23 17
Cardio vascular System Low calcium 2 7
Hypertension 34 32 High cholesterol 17 8
Tachycardia 11 9      
*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.

There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE (sargramostim) and placebo-treated patients.

Adverse events observed for the patients treated with LEUKINE (sargramostim) in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with LEUKINE (sargramostim) in the graft failure study.

In uncontrolled Phase I/II studies with LEUKINE (sargramostim) in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.

Reports of events occurring with marketed LEUKINE (sargramostim) include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during LEUKINE (sargramostim) administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.

Acute Myelogenous Leukemia

Adverse events reported in at least 10% of patients who received LEUKINE (sargramostim) or placebo were as reported in Table 8.

Table 8: Percent of AML Patients Reporting Events

Events by Body System LEUKINE
( n =52)
Placebo
(n=47)
Events by Body System LEUKINE
(n=52)
Placebo
(n =47)
Body, General Metabolic/Nutritional Disorder
Fever (no infection) 81 74 Metabolic 58 49
Infection 65 68 Edema 25 23
Weight loss 37 28 Respiratory System
Weight gain 8 21 Pulmonary 48 64
Chills 19 26 Hemic and LymphaticSystem
Allergy 12 15 Coagulation 19 21
Sweats 6 13 Cardiovascular System
Digestive System Hemorrhage 29 43
Nausea 58 55 Hypertension 25 32
Liver 77 83 Cardiac 23 32
Diarrhea 52 53 Hypotension 13 26
Vomiting 46 34 Urogenital System
Stomatitis 42 43 GU 50 57
Anorexia 13 11 Nervous System
Abdominal distention 4 13 Neuro-clinical 42 53
Skin and Appendages Neuro-motor 25 26
Skin 77 45 Neuro-psych 15 26
Alopecia 37 51 Neuro-sensory 6 11

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE (sargramostim) and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE (sargramostim) group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the LEUKINE (sargramostim) and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE (sargramostim) treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE (sargramostim) treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE (sargramostim) was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15

Antibody Formation

Serum samples collected before and after LEUKINE (sargramostim) treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE (sargramostim) by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE (sargramostim) and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn's disease receiving LEUKINE (sargramostim) by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE (sargramostim) secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with LEUKINE (sargramostim) but the rate of occurrence of antibodies in such patients has not been assessed.

Read the Leukine (sargramostim) Side Effects Center for a complete guide to possible side effects

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Interactions

Interactions between LEUKINE (sargramostim) and other drugs have not been fully evaluated. Drugs which may potentiate the myelo proliferative effects of LEUKINE (sargramostim) , such as lithium and corticosteroids, should be used with caution.

REFERENCES

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.

Read the Leukine Drug Interactions Center for a complete guide to possible interactions

Learn More »

This monograph has been modified to include the generic and brand name in many instances.

Warnings

Pediatric Use

Benzyl alcohol is a constituent of liquid LEUKINE (sargramostim) and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE (sargramostim) ) or lyophilized LEUKINE (sargramostim) reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fluid Retention

Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE (sargramostim) administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE (sargramostim) at a dose of 250 mcg/m²/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE (sargramostim) vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE (sargramostim) , the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE (sargramostim) may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE (sargramostim) has been reversible after interruption or dose reduction of LEUKINE (sargramostim) with or without diuretic therapy. LEUKINE (sargramostim) should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms

Sequestration of granulocytes in the pulmonary circulation has been documented following LEUKINE (sargramostim) infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE (sargramostim) . Special attention should be given to respiratory symptoms during or immediately following LEUKINE (sargramostim) infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE (sargramostim) administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE (sargramostim) should be administered with caution in patients with hypoxia.

Cardiovascular Symptoms

Occasional transient supra ventricular arrhythmia has been reported in uncontrolled studies during LEUKINE (sargramostim) administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE (sargramostim) . LEUKINE (sargramostim) should be used with caution in patients with preexisting cardiac disease.

Renal and Hepatic Dysfunction

In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE (sargramostim) has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE (sargramostim) administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (sargramostim) (250 mcg/m²/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE (sargramostim) administration.

Precautions

General

Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE (sargramostim) therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE (sargramostim) in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

Stimulation of marrow precursors with LEUKINE (sargramostim) may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm³ or if the platelet count exceeds 500,000/mm³, LEUKINE (sargramostim) administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE (sargramostim) therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential

LEUKINE (sargramostim) is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE (sargramostim) can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during LEUKINE (sargramostim) treatment, LEUKINE (sargramostim) therapy should be discontinued.

LEUKINE (sargramostim) has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed in patients with MDS.

Use in Patients Receiving Purged Bone Marrow

LEUKINE (sargramostim) is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE (sargramostim) . When the bone marrow purging process preserves a sufficient number of progenitors ( > 1.2 x 104/kg), a beneficial effect of LEUKINE (sargramostim) on myeloid engraftment has been reported.16

Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy

In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE (sargramostim) on myeloid reconstitution may be limited.

Use in Patients with Malignancy Undergoing LEUKINE (sargramostim) -Mobilized PBPC Collection

When using LEUKINE (sargramostim) to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.

Information for Patients

LEUKINE (sargramostim) should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE (sargramostim) may be used outside of the hospital or office setting, persons who will be administering LEUKINE (sargramostim) should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (sargramostim) (see PRECAUTIONS, Pregnancy Category C).

Laboratory Monitoring

LEUKINE (sargramostim) can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm³; ANC > 20,000 cells/mm³), a CBC is recommended twice per week during LEUKINE (sargramostim) therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE (sargramostim) administration. Body weight and hydration status should be carefully monitored during LEUKINE (sargramostim) administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted with LEUKINE (sargramostim) to evaluate the carcinogenic potential or the effect on fertility.

Pregnancy (Category C)

Animal reproduction studies have not been conducted with LEUKINE (sargramostim) . It is not known whether LEUKINE (sargramostim) can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE (sargramostim) should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether LEUKINE (sargramostim) is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE (sargramostim) should be administered to a nursing woman only if clearly needed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE (sargramostim) does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE (sargramostim) in clinical trials at doses ranging from 60-1,000 mcg/m²/day intravenously and 4-1,500 mcg/m²/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m²/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE (sargramostim) ) or lyophilized LEUKINE (sargramostim) reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS).

Geriatric Use

In the clinical trials, experience in older patients (age ≥ 65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE (sargramostim) in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out.

REFERENCES

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 auto grafts. Blood 1989; 73(3):849-857.

This monograph has been modified to include the generic and brand name in many instances.

OverDose

The maximum amount of LEUKINE (sargramostim) that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m²/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm³ were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE (sargramostim) .

In case of overdosage, LEUKINE (sargramostim) therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

ContrainDications

LEUKINE (sargramostim) is contraindicated:

  1. in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood ( ≥ 10%);
  2. in patients with known hypersensitivity to GM-CSF, yeast derived products or any component of the product;
  3. for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE (sargramostim) should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE (sargramostim) and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE (sargramostim) . The patients randomized to LEUKINE (sargramostim) had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11

REFERENCES

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.

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

General

GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid derived dendritic cells.

GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multi lineage factor and, in addition to dose-dependent effects on the myelo monocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors.1 However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2

In vitro Studies of LEUKINE (sargramostim) in Human Cells

The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of LEUKINE (sargramostim) . In vitro exposure of human bone marrow cells to LEUKINE (sargramostim) at concentrations ranging from 1-100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocyte-macrophage colonies.3 Chemotactic, anti-fungal and anti-parasitic4 activities of granulocytes and monocytes are increased by exposure to LEUKINE (sargramostim) in vitro. LEUKINE (sargramostim) increases the cytotoxicity of monocytes toward certain neoplastic cell lines3 and activates polymorpho nuclear neutrophils to inhibit the growth of tumor cells.

In vivoPrimate Studies of LEUKINE (sargramostim)

Pharmacology/toxicology studies of LEUKINE (sargramostim) were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day x 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day x 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1-2 week recovery period.

Pharmacokinetics

Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized LEUKINE (sargramostim) , at the recommended dose of 250 mcg/m², have been determined to be bioequivalent based on the statistical evaluation of AUC.5

When LEUKINE (sargramostim) (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of LEUKINE (sargramostim) infusion. For liquid LEUKINE (sargramostim) , the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m² and the mean AUC (0-inf) was 640 ng/mL•min. Corresponding results for lyophilized LEUKINE (sargramostim) in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m², and mean AUC (0-inf) of 677 ng/mL•min. GM-CSF was last detected in blood samples obtained at three or six hours.

When LEUKINE (sargramostim) (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and LEUKINE (sargramostim) remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid LEUKINE (sargramostim) , the mean clearance was 549 mL/min/m² and the mean AUC (0-inf) was 549 ng/mL•min. For lyophilized LEUKINE (sargramostim) , the mean clearance was 529 mL/min/m² and the mean AUC (0-inf) was 501 ng/mL•min.

Clinical Experience

Acute Myelogenous Leukemia

The safety and efficacy of LEUKINE (sargramostim) in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of LEUKINE (sargramostim) in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55-70 years of age, receiving induction with or without consolidation.6 A combination of standard doses of daunorubicin (days 1-3) and ara-C (days 1-7) was administered during induction and high dose ara-C was administered days 1-6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with < 5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with < 5% blasts on day 10 or four days following the second cycle of induction chemotherapy, LEUKINE (sargramostim) (250 mcg/m²/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥ 1500/mm³ for three consecutive days was attained or a maximum of 42 days. LEUKINE (sargramostim) or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3-6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.

LEUKINE (sargramostim) significantly shortened the median duration of ANC < 500/mm³ by 4 days and < 1000/mm³ by 7 days following induction (see Table 1). 75% of patients receiving LEUKINE (sargramostim) achieved ANC > 500/mm³ by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; LEUKINE (sargramostim) significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet ( > 20,000/mm³) and RBC transfusion independence were not significantly different between treatment groups.

Table 1: Hematological Recovery (in Days): Induction

 

Dataset sargramostim
n=52*
Median (25%, 75%)
Placebo
n=47
Median (25%, 75%)
p-value**
ANC > 500/m m³ a 13 (11, 16) 17 (13, 25) 0.0 09
ANC > 1000/m m³ b 14 (12, 18) 21 (13, 34) 0.0 03
PLT > 20,0 00/m m³ c 11 (7, 14) 12 (9, > 42) 0.10
RBCd 12 (9, 24) 14 ( 9 , 42) 0.53
* Patients with missing data censored.
a 2 patients on sargramostim and 4 patients on placebo had missing values.
b 2 patients on sargramostim and 3 patients on placebo had missing values.
c 4 patients on placebo had missing values.
d 3 patients on sargramostim and 4 patients on placebo had missing values.
** p=Generalized Wilcoxon

During the consolidation phase of treatment, LEUKINE (sargramostim) did not shorten the median time to recovery of ANC to 500/mm³ (13 days) or 1000/mm³ (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.

The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received LEUKINE (sargramostim) . During induction or consolidation, 27 of 52 patients receiving LEUKINE (sargramostim) and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving LEUKINE (sargramostim) and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the LEUKINE (sargramostim) arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

Disease outcomes were not adversely affected by the use of LEUKINE (sargramostim) . The proportion of patients achieving complete remission (CR) was higher in the LEUKINE (sargramostim) group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received LEUKINE (sargramostim) and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving LEUKINE (sargramostim) and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of LEUKINE (sargramostim) treatment on response or survival.

Mobilization and Engraftment of PBPC

A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post transplant were compared between four groups of patients (n=196) receiving LEUKINE (sargramostim) for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received LEUKINE (sargramostim) . The cohorts differed by dose (125 or 250 mcg/m²/day), route (IV over 24 hours or SC) and use of LEUKINE (sargramostim) post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm³. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 x 108/kg body weight) and a minimum number of phereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm³ by day five, another cytokine was substituted for LEUKINE (sargramostim) ; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post transplant effects were seen in patients administered the higher dose of LEUKINE (sargramostim) (250 mcg/m²) either IV (n=63) or SC (n=41).

PBPCs from patients treated at the 250 mcg/m²/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 x 104 CFUGM/ kg for all LEUKINE (sargramostim) -mobilized patients, compared to 0.96 x 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 x 104/kg for patients mobilized with 250 mcg/m² doses of LEUKINE (sargramostim) administered SC vs. 1.63 x 104/kg for non mobilized patients).

After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC > 500/mm³) was more rapid in patients administered LEUKINE (sargramostim) following PBPC transplantation with LEUKINE (sargramostim) -mobilized cells (see Table 2). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non mobilized subjects.

Table 2: ANC and Platelet Recovery after PBPC Transplant

  Route for Mobilization Post-transplant LEUKINE ENGRAFTMENT
(median value in days)
ANC > 500/mm³ Last platelet transfusion
No Mobilization - no 29 28
LEUKINE 250 mcg/m² V I no 21 24
V I yes 12 19
SC yes 12 17

A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. LEUKINE (sargramostim) was given SC at 250 mcg/m²/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of LEUKINE (sargramostim) administration and continued until the targeted MNC count of 9 x 108/kg or CD34+ cell count of 1 x 106/kg was reached. There was no difference in CD34+ cell count in patients receiving LEUKINE (sargramostim) once or twice a day. The median time to ANC > 500/mm³ was 12 days and to platelet recovery ( > 25,000/mm³) was 23 days.

Survival studies comparing mobilized study patients to the non mobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.

Autologous Bone Marrow Transplantation7

Following a dose ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies,8, 9 three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of LEUKINE (sargramostim) for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 LEUKINE (sargramostim) , 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120-150 mg/kg) and total body irradiation (total dose 1,200-1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m²) and carmustine (300 mg/m²), cyclophosphamide (140-150 mg/kg), hydroxyurea (4.5 grams/m²) and etoposide (375-450 mg/m²).

Compared to placebo, administration of LEUKINE (sargramostim) in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of LEUKINE (sargramostim) . This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial LEUKINE (sargramostim) treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.

Table 3: Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials of Responses in Patients with NHL and ALL

Median Values (days)
  ANC ≥ 500/m m³ ANC ≥ 100 0/mm³ Duration of Hospitalization Duration of Infection Duration of Antibacterial Therapy
LEUKINE (n=54) 18*# 24*# 25* 1* 21*
Placebo (n=50) 24 32 31 4 25
* p < 0.05 Wilcoxon or CMH ridit chi-squared # p < 0.05 Log rank
Note: The single AML patient was not included.

Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)

Myeloid engraftment (absolute neutrophil count [ANC] ≥ 500 cells/mm³) in 54 patients receiving LEUKINE (sargramostim) was observed 6 days earlier than in 50 patients treated with placebo (see Table 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the LEUKINE (sargramostim) group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever > 38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with LEUKINE (sargramostim) . The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with LEUKINE (sargramostim) than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post transplantation. As a group, leukemic subjects receiving LEUKINE (sargramostim) derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving LEUKINE (sargramostim) engrafted earlier than controls.

Patients with Hodgkin's Disease

If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. LEUKINE (sargramostim) treated patients engrafted earlier (by five days) than the placebo treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).

Allogeneic Bone Marrow Transplantation

A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of LEUKINE (sargramostim) for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 LEUKINE (sargramostim) , 56 placebo) were enrolled in the study. Twenty-three patients (11 LEUKINE (sargramostim) , 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid. Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of LEUKINE (sargramostim) significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see Table 4).

Table 4: Allogeneic BMT: Analysis of Data from Placebo-Controlled Clinical Trial

View Enlarged Table

Median time to myeloid engraftment (ANC ≥ 500 cells/mm³) in 53 patients receiving LEUKINE (sargramostim) was 4 four days less than in 56 patients treated with placebo (see Table 4). The number of patients with bacteremia and infection was significantly lower in the LEUKINE (sargramostim) group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the LEUKINE (sargramostim) group (4/53) compared to the placebo group (16/56) at p < 0.05. LEUKINE (sargramostim) -treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.

Bone Marrow Transplantation Failure or Engraftment Delay

A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether LEUKINE (sargramostim) improved survival after BMT failure.

Three categories of patients were eligible for this study:

  1. patients displaying a delay in engraftment (ANC ≤ 100 cells/mm³ by day 28 post-transplantation);
  2. patients displaying a delay in engraftment (ANC ≤ 100 cells/mm³ by day 21 post-transplantation) and who had evidence of an active infection; and
  3. patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm³ for at least one week followed by loss of engraftment with ANC < 500 cells/mm³ for at least one week beyond day 21 post-transplantation).

A total of 140 eligible patients from 35 institutions were treated with LEUKINE (sargramostim) and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.

One hundred day survival was improved in favor of the patients treated with LEUKINE (sargramostim) after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with LEUKINE (sargramostim) after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with LEUKINE (sargramostim) treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.

The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with LEUKINE (sargramostim) in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see Table 5).

Table 5: Median Survival by Multiple Organ Failure (MOF) Category

Median Survival (days)
  MOF ≤ 2 Organs MOF > 2 Organs MOF (Composite of Both Groups)
Autologous BMT
LEUKINE 474 (n =58) 78.5 ( n =10) 474 (n =68)
Historical 165 (n =14) 39 ( n =3) 161 (n=17)
Allogeneic BMT
LEUKINE 174 (n=50) 27 (n=22) 97 (n=72)
Historical 52.5 (n=60) 15.5 (n=26) 35 (n=86)
Factors that Contribute to Survival

The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.

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 Bayer HealthCare Pharmaceuticals.

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 TPA, Nuytinck JKS, et al. Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109-1115.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

IMPORTANT NOTE: Please read ALL information about LEUKINE (sargramostim) in this Patient Information Leaflet before administering any injections.

This patient package insert contains information and directions for patients and their caregivers who are receiving or giving injections of LEUKINE (sargramostim) at home. This package insert is intended to supplement discussions with your healthcare provider and does not take the place of talking with your doctor, nurse or pharmacist. If you have any questions about your treatment with LEUKINE (sargramostim) , be sure to discuss them with your healthcare team.

LEUKINE (sargramostim) ACTIONS AND USES

LEUKINE (loo'-kine) is the brand name of sargramostim (sar-gram'-oh-stim) and is also known as granulocyte- macrophage colony-stimulating factor, or GM-CSF for short. LEUKINE (sargramostim) is a man-made form of a protein, called a growth factor, that is almost identical to a protein your body makes when it is functioning normally. This growth factor helps to increase the number and function of your white blood cells, specifically neutrophils, monocytes/macrophages, and myeloid-derived dendritic cells. White blood cells, which are made in your bone marrow (the soft center of your bone), fight infections from bacteria, fungi, and viruses by surrounding and destroying them. White blood cells also help to repair tissues by removing dead and damaged cells.

If your white blood cell count (the number of white blood cells in your blood) falls to a very low level, your chance of getting an infection increases. The purpose of using LEUKINE (sargramostim) is to help your bone marrow make more white blood cells, which in turn can help your immune system recover.

LEUKINE (sargramostim) is used to help increase the number and function of white blood cells after bone marrow transplantation, in cases of bone marrow transplantation failure or engraftment delay, before and after peripheral blood stem cell transplantation, and following induction chemotherapy in older patients with acute myelogenous leukemia. Your doctor may also choose to treat other conditions with LEUKINE (sargramostim) .

Your doctor has prescribed LEUKINE (sargramostim) for you. If you are also receiving chemotherapy or radiation therapy, do not take your LEUKINE (sargramostim) in the period 24 hours before through 24 hours after the administration of your chemotherapy or radiation therapy. You may also need a blood test so that your doctor can monitor your white blood cell count and, if necessary, adjust your LEUKINE (sargramostim) dose.

POSSIBLE SIDE EFFECTS

Some patients taking LEUKINE (sargramostim) may experience unwanted side effects, most of which are mild to moderate and not serious. Not everyone who receives LEUKINE (sargramostim) will experience side effects. Some of the more common side effects include bone pain, feeling like you have the flu, feeling tired or weak, muscle aches, diarrhea, or stomach upset. You may also get a low fever (less than 100.5° F or 38° C) about one to four hours after an injection, or you may have swelling, redness, and/or discomfort where LEUKINE (sargramostim) is injected. Your doctor, nurse, or pharmacist will tell you about other possible side effects. Many of these side effects can be reduced or eliminated. Talk to your doctor, nurse, or pharmacist about what you should do if any of these things happen to you.

Some side effects or symptoms may be serious. These may be due to LEUKINE (sargramostim) , your illness, or other treatments you may have received. Call your doctor immediately if any of the following happen to you:

  • You develop a high fever (over 100.5° F or 38° C).
  • You notice any signs of infection including chills, sore throat, or congestion (such as a stuffy nose).
  • You have trouble breathing, or you develop wheezing, fainting, extensive skin rash, hives, or feel you are having an allergic reaction (see ALLERGY TO LEUKINE (sargramostim) section below).
  • You experience sudden weight gain or other signs of fluid build-up such as swollen legs or feet.
  • You develop chest pain, chest discomfort, or a rapid or irregular pulse.

If you are concerned about any other side effects or symptoms you may be having, contact your doctor, nurse, or pharmacist.

ALLERGY TO LEUKINE (sargramostim)

A generalized allergy is an uncommon but potentially serious reaction to LEUKINE (sargramostim) . This may include a skin rash over your entire body, hives, trouble breathing, a fast pulse, sweating, and feeling faint. In severe cases a generalized allergy may be life-threatening. If you think you are having a generalized allergy to LEUKINE (sargramostim) , stop taking LEUKINE (sargramostim) and notify your doctor immediately.

USAGE IN PREGNANCY AND BREAST FEEDING

If you are pregnant, are trying to become pregnant, or are breast-feeding, you should consult your doctor before taking LEUKINE (sargramostim) .

STORAGE OF LEUKINE (sargramostim)

LEUKINE (sargramostim) should be stored in the refrigerator but not in the freezer compartment. Do not shake LEUKINE (sargramostim) . Do not use LEUKINE (sargramostim) that has been frozen. Keep LEUKINE (sargramostim) out of direct sunlight. Do not use LEUKINE (sargramostim) beyond the expiration date printed on the vial label. Once the vial has been used, any remaining LEUKINE (sargramostim) should be stored in the refrigerator and used within 20 days (be sure to mark down the date you first used the vial). Throw away any remaining LEUKINE (sargramostim) after 20 days.

INSTRUCTIONS FOR PREPARING AND GIVING A SELF-INJECTION

Use the correct syringe and dose

If your doctor has recommended that you take LEUKINE (sargramostim) at home, your doctor, nurse, or pharmacist should have instructed you and/or your caregiver on how LEUKINE (sargramostim) should be prepared, how it should be injected, and how often it should be injected.

The dose will usually be measured in milliliters (mL) or cubic centimeters (cc). (For example: 0.8 mL or 0.8 cc). It is important that you use a syringe that is marked in tenths (1/10) of a milliliter or cubic centimeter (for example: 0.1, 0.2, 0.3, 0.4, 0.5, etc. ... to 1.0 mL or cc) so that you are able to measure the correct dose prescribed by your doctor. A 3 cc syringe with a 25 to 30 gauge 5/8-inch needle or the syringe and needle size specified by your doctor may be used. Your doctor will either supply you with the correct syringes and needles, or will write you a prescription so you can get the correct syringes and needles from your pharmacy.

 

Use the correct syringe and dose - Illustration

It is very important that you use the correct needle and syringe. Failure to use the correct syringe could result in your receiving either too little or too much LEUKINE (sargramostim) . If you receive too little LEUKINE (sargramostim) , it may not be effective. If you receive too much LEUKINE (sargramostim) , your white blood cell count may get too high, which may be harmful.

Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist.

INJECTION SITE

Choosing an Injection Site

Your doctor, nurse, or pharmacist has instructed you on how to give yourself a subcutaneous (under the skin) injection of LEUKINE (sargramostim) . The best areas for self-injecting LEUKINE (sargramostim) are the thighs or stomach. The navel and waistline should be avoided. If a care-giver is helping with the injections, you may be instructed to inject on the back portion of the upper arms. It is a good idea to know where your injection will be given before you prepare your dose.

 

Choosing an Injection Site - Illustration

Rotating Injection Sites

It is important to use a different injection site each time to avoid soreness in any one area. A new injection should not be given in the same area as the last injection. It is a good idea to alternate your injection sites from one thigh to the stomach and then to the other thigh. This is called rotating your injection sites. Injection sites should be at least one inch apart. Do not choose an area where the skin is tender, bruised, red, or hard. To keep track of your injection sites, keep a record of where and when you give yourself an injection. One way to do that is to note the injection site on a calendar or in a diary along with the date you first used the vial. If all areas become tender, talk to your doctor, nurse, or pharmacist about choosing other injection sites.

Injection Site Skin Reactions

Occasionally a skin reaction may occur at the injection site. This usually will not require you to stop taking LEUKINE (sargramostim) . The skin may become red, painful, or swollen. If a skin reaction occurs, contact your doctor. The following steps may be taken to help prevent further skin reactions:

  • At least 30 minutes before you plan to inject, remove your LEUKINE (sargramostim) from the refrigerator and allow it to come to room temperature before injecting.
  • Rotate the injection sites from one injection to the next.
  • Apply ice to the site for one minute immediately prior to injection.
  • Inject LEUKINE (sargramostim) slowly.
  • Avoid rubbing the skin before or after injecting.

GIVING YOURSELF AN INJECTION

Before using LEUKINE (sargramostim) for the first time, talk to your doctor, nurse, or pharmacist about how to use it, what to expect when using it, possible side effects, and what to do if side effects occur. You must be instructed and trained properly in how to prepare and inject LEUKINE (sargramostim) by your doctor, nurse, or pharmacist prior to using it. Do not attempt to self-administer LEUKINE (sargramostim) until you are sure that you understand the instructions for giving an injection to yourself. Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. If you are unsure about the amount (mL or cc) or dose to be used, how to inject yourself, or how often to inject yourself, talk to your doctor, nurse, or pharmacist.

IMPORTANT: IT IS VERY IMPORTANT THAT YOU CAREFULLY READ THESE INSTRUCTIONS AND FOLLOW THEM EXACTLY IN ORDER TO HELP AVOID CONTAMINATION OF THE LEUKINE (sargramostim) AND POSSIBLE INFECTION.

Remove LEUKINE (sargramostim) From the Refrigerator and Inspect the Vial and Contents

1. Take the LEUKINE (sargramostim) vial out of the refrigerator at least 30 minutes before you plan to inject, allowing it to come to room temperature. Do not leave the vial in direct sunlight.

2. Check the date on the label to make sure the LEUKINE (sargramostim) has not expired; if it has, contact your doctor, nurse, or pharmacist for further instructions. LEUKINE (sargramostim) should be clear and colorless. If it is not, or if the LEUKINE (sargramostim) appears to contain lumps, flakes, or particles, contact your doctor, nurse, or pharmacist.

3. DO NOT SHAKE the vial. Shaking the vial could cause froth or bubbles to appear. Although this will not affect how well LEUKINE (sargramostim) will work, it could decrease the amount of LEUKINE (sargramostim) that you are able to draw into the syringe. If the LEUKINE (sargramostim) looks frothy or bubbly, use another vial. Return the frothy or bubbly vial to the refrigerator and allow it to settle for use on another day.

Gather Your Supplies and Prepare Your Work Area

4. Select a clean, convenient, well-lit location to lay out your supplies. It is a good idea to wipe down the area with an alcohol swab to make sure it is germ-free. Gather the following supplies along with the LEUKINE (sargramostim) :

  • A sterile syringe and needle (as specified by your doctor, nurse, or pharmacist)
  • Prepackaged alcohol swabs
  • Ice pack
  • A puncture-resistant container for disposal of the needle and syringe (see Step 22 regarding proper disposal container)

 

Gather Your Supplies and Prepare Your Work Area - Illustration

Choose and Prepare the Injection Site

5. Wash your hands thoroughly with soap and warm water, and dry them with a clean towel.

This should be done just before cleaning the injection site and preparing the LEUKINE (sargramostim) dose.

 

Wash your hands thoroughly with soap and warm water, and dry them with a
  clean towel - Illustration

6. Choose an injection site. Do not choose an area where the skin is tender, bruised, red, or hard. As you have been instructed, choose a different site with each injection. Today's injection should not be given in the same area as your last injection. To keep track of your injection sites, you may want to record the injection site you picked on a calendar or in a diary. For additional information, please refer to the INJECTION SITE section above.

7. Ice the site for about 1 minute before your injection. Then, with an alcohol swab, wipe the skin where the injection will be made using a gentle circular motion. Allow the skin to dry for about 10 seconds. Set the used alcohol swab aside. Do not re-use this alcohol swab.

 

Ice the site for about 1 minute before your injection - Illustration

Withdraw the LEUKINE (sargramostim) From the Vial

8. The LEUKINE (sargramostim) should now be at room temperature. DO NOT SHAKE the vial.

9. Flip off the plastic cap from the LEUKINE (sargramostim) vial. Do not remove the gray rubber stopper.

10. Wipe the top of the rubber stopper with a new alcohol swab. Set the used alcohol swab aside. Do not touch the rubber stopper with your hands or fingers. If you do touch the stopper, clean it again with a new alcohol swab.

 

Withdraw the LEUKINE From the Vial - Illustration

11. Remove the syringe and needle specified by your doctor from its packaging. With the cover still on the needle, draw air into the syringe by pulling back on the plunger. The amount of air you draw into the syringe should be equal to your LEUKINE (sargramostim) dose.

 

Remove the syringe and needle specified - Illustration

12. Carefully remove the needle cover. Do not lay down the syringe or allow the needle to touch anything. If the needle touches any surface, including your hands, throw away the needle and syringe in your disposal container and start over (at Step 11) with a new syringe and needle.

13. With the vial upright, insert the needle downward, through the center of the gray rubber stopper. After the needle penetrates the gray rubber stopper, push the plunger all the way in to inject the air into the vial. Make sure the needle is above the LEUKINE (sargramostim) . Try not to inject the air into the LEUKINE (sargramostim) because bubbles may form, making it hard for you to withdraw the correct LEUKINE (sargramostim) dose. The air you just injected into the vial will make it easier for you to withdraw the LEUKINE (sargramostim) into the syringe. Leave the needle in the rubber stopper.

 

With the vial upright, insert the needle downward  - Illustration

14. Without withdrawing the needle from the rubber stopper, turn the vial upside down. Then, move the needle tip into the LEUKINE (sargramostim) . Now slowly pull back on the plunger until the correct dose of LEUKINE (sargramostim) is in the syringe.

 

Without withdrawing the needle from the rubber stopper, turn the vial upside down  - Illustration

15. Before withdrawing the needle from the rubber stopper, be sure there are no air bubbles in the syringe. The air bubbles are harmless but they can decrease the amount of LEUKINE (sargramostim) you receive. If there are air bubbles, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. To remove air bubbles, gently push some of the solution back into the vial. Now slowly pull back on the plunger until the correct dose of LEUKINE (sargramostim) is in the syringe. Repeat this procedure as needed until you can draw up the correct dose of LEUKINE (sargramostim) without air bubbles.

16. Withdraw the needle from the rubber stopper. Do not lay down the syringe or allow the needle to touch anything.

Inject the LEUKINE (sargramostim)

17. With one hand, gently smooth the skin of the injection site (the area you wiped with the alcohol swab) between your thumb and forefinger so it is taut.

18. With your other hand, hold the syringe, just like a pencil, at a 90 degree angle to the skin, about 2 inches above the surface of the skin. Using a quick, short motion, insert the needle.

 

Inject the LEUKINE - Illustration

19. Release your grasp on the skin. Gently pull back on the plunger just a little bit (about 1/8 of an inch). If you do not see blood in the syringe, slowly inject all of the LEUKINE (sargramostim) by pushing the plunger all the way down.

 

Slowly inject all of the LEUKINE by pushing the plunger  - Illustration

If you see blood in the syringe, do not inject LEUKINE (sargramostim) . Withdraw the needle at the same angle it was inserted. Finding blood in the syringe simply means you hit a blood vessel rather than the fatty tissues you need to inject into, and is not a cause for concern. Discard the syringe in a puncture-resistant container. Repeat the steps to prepare a new syringe. Choose, clean, and ice a new injection site. Remember to check again for blood before injecting LEUKINE (sargramostim) .

20. Remove the needle at the same angle as it was inserted.

21. Lightly touch an alcohol swab over the injection site until any bleeding has stopped. Do not rub or press the site because doing so may irritate the area.

 

Lightly touch an alcohol swab over the injection site - Illustration

Dispose of Supplies

22. It is extremely important that you do not reuse syringes or needles. Do not attempt to put the needle cover back on the needle. Throw away used syringes and needles in a puncture-resistant container as instructed by your doctor, nurse, or pharmacist. They may be able to supply you with a container made specifically for disposing of used syringes and needles. If not, then you may use the following:

  • A hard plastic container that you cannot see through with a screw-on cap, such as an empty bleach or laundry detergent bottle. Always screw the cap on tightly after disposing of your syringes and needles. Do not recycle the container.
  • A metal container with a plastic lid, such as a coffee can. Cut a hole in the plastic lid and tape the lid to the metal container.
  • DO NOT use a glass or clear plastic container, or any container that will be recycled or returned to a store.

 

Dispose of Supplies - Illustration

23. Keep the container out of the reach of children. Make sure the container is properly labeled as to its content. When the container is about two-thirds (2/3) full, dispose of it as instructed. There may be special state and local laws regarding the proper disposal of needles and syringes that your doctor, nurse, or pharmacist may discuss with you.

24. Throw away empty LEUKINE (sargramostim) vials and used alcohol swabs in the trash, unless otherwise instructed.

25. If the vial has any remaining LEUKINE (sargramostim) , return the used vial to the refrigerator for use the next day. Do not freeze. Used vials containing LEUKINE (sargramostim) should be stored in the refrigerator and used within 20 days (be sure to mark down the date you first used the vial). After 20 days, throw away any remaining LEUKINE (sargramostim) .

IMPORTANT NOTES

  1. Follow the instructions given to you by your doctor, nurse, or pharmacist. Do not make any changes in your dose or how often you give yourself LEUKINE (sargramostim) . If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist.
  2. Try to get into a routine; give yourself LEUKINE (sargramostim) at the same time each day.
  3. Keep LEUKINE (sargramostim) and all supplies out of the reach of children.
  4. If any of the following happens to you, contact your doctor, nurse, or pharmacist:
  • You miss a dose of LEUKINE (sargramostim) .
  • You notice anything unusual about your condition while you are taking LEUKINE (sargramostim) .
  • You develop a high fever (over 100.5° F or 38° C).
  • You notice any signs of infection, including chills, sore throat, or congestion (such as a stuffy nose).

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

SARGRAMOSTIM - INJECTION

 

(sarr-GRAM-oh-stim)

 

COMMON BRAND NAME(S): Leukine

 

USES: This medication is given to those whose ability to make white blood cells has been reduced. This medication stimulates the blood system (bone marrow) to make white blood cells, which help your body fight infections. Sargramostim (also known as GM-CSF, or granulocyte-macrophage colony stimulating factor) is a man-made version of a certain natural substance found in the body that also stimulates the bone marrow to make white blood cells. It is produced using a certain yeast (Saccharomyces cerevisiae).

 

HOW TO USE: Do not shake this medication. Doing so may make the drug ineffective.

Follow your doctor's directions exactly. This medication is given by infusion into a vein (IV) or by injection under the skin as directed by your doctor, usually once a day until the proper blood counts are reached. Dosage is based on your medical condition, body size, lab results, and response to treatment. Use the exact amount of drug prescribed by your doctor. If you use less than the prescribed amount, your body may not produce enough white blood cells to protect your body against infections. If you use more than the prescribed amount, your body may produce too many white blood cells.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day.

When injecting under the skin, a new injection site should be chosen for each dose. This will help prevent soreness. Never inject sargramostim into skin that is tender, red, bruised, or hard or has scars or stretch marks.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Remove the medication from the refrigerator 30 minutes before you inject it to allow it to reach room temperature. Do not shake. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

If you are receiving chemotherapy for cancer, you should not be given sargramostim at the same time. You should receive sargramostim either before or after the chemotherapy, depending on your blood count results and your doctor's directions.

Consumer Overview Side Effect

SIDE EFFECTS: Aching in the bones and muscles, chills, or headache may occur. Taking a non-aspirin pain reliever such as acetaminophen may help. Ask your doctor or pharmacist for more details. Nausea, vomiting, or injection-site reactions such as redness, swelling, itching, lumps, or bruising may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: chest pain, sudden weight gain, swelling of the hands/feet, shortness of breath, black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, fast/irregular heartbeat, vision problems, a sudden reddening of the face/neck/chest, severe dizziness, fainting.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Leukine (sargramostim) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before using sargramostim, tell your doctor or pharmacist if you are allergic to it; or to other medications made in a similar manner (man-made proteins using Saccharomyces cerevisiae); or if you have any other allergies. This product may contain inactive ingredients (such as benzyl alcohol), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: fluid retention, lung problems, heart problems (e.g., congestive heart failure-CHF, rhythm problems), liver disease, kidney disease, other blood disorders (e.g., myeloid cancers), current chemotherapy.

If you are scheduled to have radiation therapy, tell your doctor you are taking sargramostim. This medication should not be given during the time you are receiving radiation therapy.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: corticosteroids (e.g., prednisone), lithium.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: shortness of breath, unusual weakness, fast heartbeat.

 

NOTES: This medication must be taken under close medical supervision so your blood counts can be monitored. Keep all medical appointments. Laboratory and/or medical tests (e.g., blood counts, platelet counts, liver function, kidney function, body weight, fluid status) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store in the refrigerator between 36-46 degrees F (2-8 degrees C). Do not freeze. After mixing, use within time period indicated in the product instructions or consult your pharmacist. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

 

Information last revised December 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Leukine

Generic Name: sargramostim (Pronunciation: sar GRA moe stim)

  • What is sargramostim (Leukine)?
  • What are the possible side effects of sargramostim (Leukine)?
  • What is the most important information I should know about sargramostim (Leukine)?
  • What should I discuss with my healthcare provider before using sargramostim (Leukine)?
  • How should I use sargramostim (Leukine)?
  • What happens if I miss a dose (Leukine)?
  • What happens if I overdose (Leukine)?
  • What should I avoid while using sargramostim (Leukine)?
  • What other drugs will affect sargramostim (Leukine)?
  • Where can I get more information?

What is sargramostim (Leukine)?

Sargramostim is a man-made form of a protein that stimulates the growth of white blood cells in your body. White blood cells help your body fight against infection.

Sargramostim is used to increase white blood cells and help prevent serious infection in conditions such as leukemia, bone marrow transplant, and pre-chemotherapy blood cell collection. Sargramostim is for use in adults who are at least 55 years old.

Sargramostim may also be used for purposes not listed in this medication guide.

What are the possible side effects of sargramostim (Leukine)?

Some people receiving a sargramostim injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, short of breath, or have a fast heartbeat, chest tightness, or trouble breathing during the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • high fever, chills, sore throat, stuffy nose, flu symptoms;
  • white patches or sores inside your mouth or on your lips;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • swelling, rapid weight gain;
  • chest pain, fast or uneven heart rate;
  • weakness or fainting;
  • black, bloody, or tarry stools;
  • coughing up blood or vomit that looks like coffee grounds;
  • painful or difficult urination;
  • dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • breathing problems; or
  • problems with vision, speech, balance, or memory.

Less serious side effects may include:

  • nausea, stomach pain, vomiting, diarrhea, loss of appetite;
  • tired feeling;
  • hair loss;
  • weight loss;
  • headache;
  • mild skin rash or itching;
  • bone pain;
  • joint or muscle pain; or
  • redness, swelling, or irritation where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Leukine (sargramostim) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about sargramostim (Leukine)?

You should not use this medication if you are allergic to sargramostim or to yeast. Sargramostim should not be used within 24 hours before or after you receive chemotherapy or radiation.

Before you receive sargramostim, tell your doctor if you have fluid retention (especially around your lungs), heart disease, high blood pressure, congestive heart failure, bone marrow cancer, a seizure disorder, liver or kidney disease, or a breathing disorder such as COPD or asthma.

Tell your caregiver right away if you feel dizzy, nauseated, light-headed, short of breath, or have a fast heartbeat, chest tightness, or trouble breathing when you inject this medication.

Call your doctor at once if you have any other serious side effects such as fever, chills, sore throat, flu symptoms, mouth sores, easy bruising or bleeding, and swelling or rapid weight gain.

Using sargramostim may increase your risk of developing other cancers. Ask your doctor about your individual risk.

Side Effects Centers
  • Leukine

Patient Detailed How Take

What should I discuss with my healthcare provider before using sargramostim (Leukine)?

You should not use this medication if you are allergic to sargramostim or to yeast. Sargramostim should not be used within 24 hours before or after you receive chemotherapy or radiation.

To make sure you can safely use sargramostim, tell your doctor if you have any of these other conditions:

  • fluid retention;
  • a buildup of fluid around your lungs (also called pleural effusion);
  • bone marrow cancer;
  • heart disease, high blood pressure; congestive heart failure;
  • epilepsy or other seizure disorder;
  • liver or kidney disease; or
  • asthma, chronic obstructive pulmonary disease (COPD), or other breathing problems.

Using sargramostim may increase your risk of developing other cancers. Ask your doctor about your individual risk.

FDA pregnancy category C. It is not known whether sargramostim will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether sargramostim passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use sargramostim (Leukine)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Sargramostim should not be used within 24 hours before or after you receive chemotherapy or radiation.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Sargramostim is injected into a vein or under the skin. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, syringes, IV tubing, and other items used to inject the medicine.

When injected into a vein, sargramostim must be given slowly. The IV infusion can take up to 24 hours to complete.

Use a different place on your stomach, thigh, or upper arm each time you give the injection under the skin. Just before you give the injection, apply an ice pack to the skin for one minute. Your care provider will show you the best places on your body to inject the medication. Do not inject into the same place two times in a row.

Sargramostim powder must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Do not shake the mixed medicine or it may foam. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.

To be sure this medication is helping your condition, your blood may need to be tested often. This will help your doctor determine how long to treat you with sargramostim. Your liver function will also need to be tested. Visit your doctor regularly.

Store the liquid medicine in the refrigerator, do not freeze. Protect from light. You may take the medicine out and allow it to reach room temperature before measuring your dose in a syringe. Then return the medicine to the refrigerator. Throw away any unused liquid after 20 days.

After mixing sargramostim powder with a diluent, store in the refrigerator and use it within 6 hours. Do not freeze. Protect from light. If you have mixed the powder with bacteriostatic water, you may store this mixture in the refrigerator for up to 20 days.

Side Effects Centers
  • Leukine

Patient Detailed Avoid Taking

What happens if I miss a dose (Leukine)?

Call your doctor for instructions if you miss a dose of sargramostim.

What happens if I overdose (Leukine)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, weakness, headache, fever, chills, skin rash, fast heart rate, or trouble breathing.

What should I avoid while using sargramostim (Leukine)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drugs will affect sargramostim (Leukine)?

Tell your doctor about all other medicines you use, especially:

  • lithium (Eskalith, Lithobid); or
  • a steroid such as prednisone (Meticorten, Sterapred), methylprednisolone (Medrol), dexamethasone (Decadron), and others.

This list is not complete and other drugs may interact with sargramostim. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about sargramostim.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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Side Effects Centers
  • Leukine

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