Leukine Information
Leukine ()
Leukine () Description
Leukine () (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast () expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. Leukine () 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 () 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 () presentation is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Leukine () 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 () has a pH range of 6.7 - 7.7 and lyophilized Leukine () has a pH range of 7.1 - 7.7.
Liquid Leukine () and reconstituted lyophilized Leukine () are clear, colorless liquids suitable for subcutaneous injection (SC) or intravenous infusion (IV).
Liquid Leukine () contains 500 mcg (2.8 x 10 IU/mL) sargramostim and 1.1% benzyl alcohol in a 1 mL solution. The vial of lyophilized Leukine () contains 250 mcg (1.4 x 10 IU/vial) sargramostim.
The liquid Leukine () vial and reconstituted lyophilized Leukine () 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 () is approximately 5.6 x 10 IU/mg.
Leukine () Clinical Pharmacology
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 multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. 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.
Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized Leukine () , at the recommended dose of 250 mcg/m, have been determined to be bioequivalent based on the statistical evaluation of AUC.
When Leukine () (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 () infusion. For liquid Leukine () , the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m and the mean AUC (0–inf) was 640 ng/mL•min. Corresponding results for lyophilized Leukine () in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m, 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 () (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 () remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid Leukine () , the mean clearance was 549 mL/min/m and the mean AUC (0-inf) was 549 ng/mL•min. For lyophilized Leukine () , the mean clearance was 529 mL/min/m and the mean AUC (0-inf) was 501 ng/mL•min.
Leukine () Indications And Usage
Leukine () is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of Leukine () have not been assessed in patients with AML under 55 years of age.
The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.
Leukine () Clinical Experience
The safety and efficacy of Leukine () 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 () 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. 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 () (250 mcg/m/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/mm for three consecutive days was attained or a maximum of 42 days. Leukine () 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 () significantly shortened the median duration of ANC <500/mm by 4 days and <1000/mm by 7 days following induction (see ). 75% of patients receiving Leukine () achieved ANC >500/mm 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 () 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/mm) and RBC transfusion independence were not significantly different between treatment groups.
During the consolidation phase of treatment, Leukine () did not shorten the median time to recovery of ANC to 500/mm (13 days) or 1000/mm (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 () . During induction or consolidation, 27 of 52 patients receiving Leukine () 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 () and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Leukine () 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 () . The proportion of patients achieving complete remission (CR) was higher in the Leukine () 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 () 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 () and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Leukine () treatment on response or survival.
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 () 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 () . The cohorts differed by dose (125 or 250 mcg/m/day), route (IV over 24 hours or SC) and use of Leukine () post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 x 10/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/mm by day five, another cytokine was substituted for Leukine () ; 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 () (250 mcg/m) either IV (n=63) or SC (n=41).
PBPCs from patients treated at the 250 mcg/m/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 10 CFU-GM/kg for all Leukine () -mobilized patients, compared to 0.96 x 10/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 10/kg for patients mobilized with 250 mcg/m doses of Leukine () administered SC vs. 1.63 x 10/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/mm) was more rapid in patients administered Leukine () following PBPC transplantation with Leukine () -mobilized cells (see ). 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.
A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Leukine () was given SC at 250 mcg/m/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 () administration and continued until the targeted MNC count of 9 x 10/kg or CD34+ cell count of 1 x 10/kg was reached. There was no difference in CD34+ cell count in patients receiving Leukine () once or twice a day. The median time to ANC>500/mm was 12 days and to platelet recovery (>25,000/mm) was 23 days.
Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.
Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies, three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of Leukine () for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 Leukine () , 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 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/m) and carmustine (300 mg/m), cyclophosphamide (140-150 mg/kg), hydroxyurea (4.5 grams/m) and etoposide (375-450 mg/m).
Compared to placebo, administration of Leukine () 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 () . 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 () 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.
A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Leukine () for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Leukine () , 56 placebo) were enrolled in the study. Twenty-three patients (11 Leukine () , 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 () significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see ).
Median time to myeloid engraftment (ANC ≥ 500 cells/mm) in 53 patients receiving Leukine () was 4 four days less than in 56 patients treated with placebo (see ). The number of patients with bacteremia and infection was significantly lower in the Leukine () 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 () group (4/53) compared to the placebo group (16/56) at p<0.05. Leukine () -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.
A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Leukine () improved survival after BMT failure.
Three categories of patients were eligible for this study:
A total of 140 eligible patients from 35 institutions were treated with Leukine () 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 () 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 () 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 () 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. Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with Leukine () in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see ).
Leukine () Contraindications
Leukine () is contraindicated:
Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Leukine () 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 () and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Leukine () . The patients randomized to Leukine () 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.
Leukine () Precautions
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 () 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 () 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 () may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm or if the platelet count exceeds 500,000/mm, Leukine () 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 () 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.
Leukine () is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Leukine () 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 () treatment, Leukine () therapy should be discontinued.
Leukine () has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.
Controlled studies have not been performed in patients with MDS.
Leukine () should be used under the guidance and supervision of a health care professional. However, when the physician determines that Leukine () may be used outside of the hospital or office setting, persons who will be administering Leukine () should be instructed as to the proper dose, and the method of reconstituting and administering Leukine () (see ). 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 ). Female patients of childbearing potential should be advised of the possible risks to the fetus of Leukine () (see
).
Leukine () Adverse Reactions
Leukine () 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 () or placebo were as reported in .
No significant differences were observed between Leukine () 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 () has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see ). In addition, there was no significant difference in relapse rate and 24 month survival between the Leukine () 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 () or placebo were as reported in .
There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the Leukine () and placebo-treated patients. Adverse events observed for the patients treated with Leukine () 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 () in the graft failure study.
In uncontrolled Phase I/II studies with Leukine () 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 () 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 ). Body weight and hydration status should be carefully monitored during Leukine () administration.
Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.
Adverse events reported in at least 10% of patients who received Leukine () or placebo were as reported in .
Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Leukine () and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Leukine () group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Leukine () 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 () 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 () treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when Leukine () 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).
The maximum amount of Leukine () that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m/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/mm 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 () .
In case of overdosage, Leukine () therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
Leukine () Dosage And Administration
The recommended dose is 250 mcg/m/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 () should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. Leukine () should be continued until an ANC >1500 cells/mm for 3 consecutive days or a maximum of 42 days. Leukine () should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.
In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm or ANC > 20,000 cells/mm) a CBC with differential is recommended twice per week during Leukine () therapy. Leukine () treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm.
The recommended dose is 250 mcg/m/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 () until the post marrow infusion ANC is less than 500 cells/mm. Leukine () should be continued until an ANC >1500 cells/mm 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 () 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/mm, ANC > 20,000 cells/mm) a CBC with differential is recommended twice per week during Leukine () therapy. Leukine () treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm.
The recommended dose is 250 mcg/m/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/m/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Leukine () should be discontinued immediately if blast cells appear or disease progression occurs.
In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm, ANC > 20,000 cells/mm) a CBC with differential is recommended twice per week during Leukine () therapy. Leukine () treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm.
Leukine () How Supplied
Liquid Leukine () is available in vials containing 500 mcg/mL (2.8 x 10 IU/mL) sargramostim. Lyophilized Leukine () is available in vials containing 250 mcg (1.4 x 10 IU/vial) sargramostim.
Each dosage form is supplied as follows:
Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Leukine () (NDC 58468-0181-1)
Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid Leukine () (NDC 58468-0181-2)
Leukine () Storage
Leukine () 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.
Leukine () 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, . Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factors. Science 1986; 232:506-508.
4. Reed SG, Nathan CF, Pihl DL, . 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, . 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, . 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, . 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, 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, . Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109-1115.
11. Bunn P, Crowley J, Kelly K, Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.
12. Herrmann F, Schulz G, Lindemann A, . 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, . Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocytemacrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.
14. Vadhan-Raj S, Keating M, LeMaistre A, . 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, . 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, administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857.
© 2009, Genzyme Corporation. All rights reserved. Leukine () is a registered trademark licensed to Genzyme Corporation.
U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation Technologies U.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763; 5,895,646; 5,891,429; and 5,720,952.
Manufactured by:
Bayer HealthCare Pharmaceuticals, LLC.
Seattle, WA 98101
US License No. 1791
Distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
Phone: 1-888-4RX-Leukine ()
Revised July 1, 2009
Leukine () Package Label - Principal Display Panel – Mcg – Vial Carton
NDC 58468-0180-2
Leukine ()
sargramostim
A Recombinant GM-CSF-Yeast-Expressed
Lyophilized
5 x 250 mcg/vial
1.4 x 10IU/vial
Sterile
Rx only
U.S. Patent Nos. 5,391,485;
5,393,870; and 5,229,496.
Licensed under Research
Corporation Technologies
U.S. Patent No. 5,602,007.
- 250 mcg
- 5 vials
- Injection
genzyme
Leukine () Package Label - Principal Display Panel – Mcg – Vial Carton
NDC 58468-0181-2
Leukine ()
sargramostim
A Recombinant GM-CSF-Yeast-Expressed
liquid injection, contains preservative
5 x 500 mcg/mL
2.8 x 10IU/mL
Sterile
Rx only
- 5 multiple
use vials
genzyme
Leukine () Package Label - Principal Display Panel – Mcg – Vial Carton – Sample
NDC 58468-0181-4
Sample-Not for sale
Leukine ()
sargramostim
A Recombinant GM-CSF-Yeast-Expressed
liquid injection, contains preservative
5 x 500 mcg/mL
2.8 x 10IU/mL
Sterile
Rx only
- 5 multiple
use vials
genzyme
