Drugs Details

Drugs Info of Leukine
Drugs Details
  • Drugs Type  : FDA
  • Date : 28th Mar 2015 02:43 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 byrecombinant 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 106IU/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 hematopoieticprogenitor 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 marrowtransplantation (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 ofantibiotic 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 (seeClinical 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 (NDC50419-002-33)

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) includearrhythmia, 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

Learn More »
 
 
 

Interactions

Interactions between LEUKINE (sargramostim) and other drugs have not been fully evaluated. Drugs which may potentiate the myelo proliferativeeffects 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 andDOSAGE 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 anymalignancy 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 vitromarrow 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 vitrodata 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) (seePRECAUTIONS, Pregnancy Category C).

Laboratory Monitoring

LEUKINE (sargramostim) can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessiveleukocytosis (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 alIn 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 orperipheral 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 concurrentthoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE (sargramostim) . The patients randomizedto LEUKINE (sargramostim) had s

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