Leukine

Acute Myeloid Leukemia Following Induction Chemotherapy

LEUKINE is indicated to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).

Autologous Peripheral Blood Progenitor Cell Mobilization and Collection

LEUKINE is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.

Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation

LEUKINE is indicated for the acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).

Allogeneic Bone Marrow Transplantation

LEUKINE is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic bone marrow transplantation from HLA-matched related donors.

Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure

LEUKINE is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous bone marrow transplantation in whom neutrophil recovery is delayed or failed.

Acute Exposure to Myelosuppressive Doses of Radiation (H-ARS)

LEUKINE is indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).

Neutrophil Recovery Following Induction Chemotherapy for Acute Myeloid Leukemia

The recommended dose is 250 mcg/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 less than 5% blasts. If a second cycle of induction chemotherapy is necessary, administer LEUKINE approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Continue LEUKINE until an absolute neutrophil count (ANC) greater than 1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ].

Dose Modifications
Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose for the following:

• Leukemic regrowth: Discontinue LEUKINE immediately
• Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or interrupt dosing until the reaction abates
• ANC greater than 20,000 cells/mm3: Interrupt LEUKINE treatment or reduce the dose by 50%

Autologous Peripheral Blood Progenitor Cell Mobilization and Collection

The recommended dose is 250 mcg/m2/day administered intravenously over 24 hours or subcutaneously once daily. 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 after 5 days of LEUKINE and performed daily until protocol specified targets were achieved [see Clinical Studies ].

If WBC greater than 50,000 cells/mm3, reduce the LEUKINE dose by 50%. Consider other mobilization therapy if adequate numbers of progenitor cells are not collected.

Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation

Autologous Peripheral Blood Progenitor Cell Transplantation

The recommended dose is 250 mcg/m2/day administered intravenously over 24 hours or subcutaneously once daily beginning immediately following infusion of progenitor cells and continuing until an ANC greater than 1500 cells/mm3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy.

Autologous Bone Marrow Transplantation

The recommended dose is 250 mcg/m2/day administered intravenously 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. Do not administer LEUKINE until the post marrow infusion ANC is less than 500 cells/mm3. Continue LEUKINE until an ANC greater than 1500 cells/mm3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ].

Allogeneic Bone Marrow Transplantation

The recommended dose is 250 mcg/m2/day administered intravenously 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. Do not administer LEUKINE until the post marrow infusion ANC is less than 500 cells/mm3. Continue LEUKINE until an ANC greater than 1500 cells/mm3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ].

Dose Modifications
Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose as for the following:

• Disease progression or blast cell appearance: Discontinue LEUKINE immediately
• Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or temporarily discontinue until the reaction abates
• WBC greater than 50,000 cells/mm3 or ANC greater than 20,000 cells/mm3: Interrupt LEUKINE treatment or reduce the dose by 50%

Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure

The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour intravenous infusion. The dose can be repeated after 7 days off therapy if neutrophil recovery has not occurred. If neutrophil recovery 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.

Dose Modifications
Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose as for the following:

• Disease progression or blast cell appearance: Discontinue LEUKINE immediately
• Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or temporarily discontinue until the reaction abates
• WBC greater than 50,000 cells/mm3 or ANC greater than 20,000 cells/mm3: Interrupt LEUKINE treatment or reduce the dose by 50%

Acute Exposure to Myelosuppressive Doses of Radiation (H-ARS)

For patients with H-ARS, the recommended dose of LEUKINE is a subcutaneous injection administered once daily as follows:

• 7 mcg/kg in adult and pediatric patients weighing greater than 40 kg
• 10 mcg/kg in pediatric patients weighing 15 kg to 40 kg
• 12 mcg/kg in pediatric patients weighing less than 15 kg

Administer LEUKINE as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).

Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.

Obtain a baseline CBC with differential and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm3 for three consecutive CBCs. Do not delay administration of LEUKINE if a CBC is not readily available.

Continue administration of LEUKINE until the ANC remains greater than 1,000/mm3 for three consecutive CBCs or exceeds 10,000/mm3 after a radiation-induced nadir.

Preparation and Administration of LEUKINE

• Do not administer LEUKINE simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy [see Warnings and Precautions ].
• LEUKINE for injection is a sterile, preservative-free lyophilized powder that requires reconstitution with 1 mL Sterile Water for Injection (without preservative), USP, to yield a clear, colorless single-dose solution or 1 mL Bacteriostatic Water for Injection, USP (with 0.9% benzyl alcohol as preservative) to yield a clear, colorless single-dose solution.

Use only LEUKINE for injection (lyophilized powder) reconstituted with Sterile Water for Injection without preservatives when administering LEUKINE to neonates or infants to avoid benzyl alcohol exposure [see Warnings and Precautions ].

Do NOT use an in-line membrane filter for intravenous infusion of LEUKINE.

• Store reconstituted solution under refrigeration at 2°C to 8°C (36°F to 46°F); DO NOT FREEZE.
• In the absence of compatibility and stability information, do not add other medication to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare intravenous infusion solutions.
• 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.

LEUKINE for Injection Preparation

Reconstitute the lyophilized powder with 1 mL of diluent. Do not mix the contents of vials reconstituted with different diluents together. Reconstitute with either Sterile Water for Injection, USP (without preservative) or Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) for intravenous or subcutaneous administration. Discard any unused portions.

• When reconstituted with Sterile Water for Injection, USP (without preservative), may store the reconstituted solution refrigerated at 2°C to 8°C and must use within 24 hours following reconstitution.
• When reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), may store the reconstituted solution refrigerated at 2°C to 8°C and must use within 20 days following reconstitution.

LEUKINE for Intravenous Administration

Dilute reconstituted LEUKINE in 0.9% Sodium Chloride Injection, USP. If the final concentration of LEUKINE is less than 10 mcg/mL, add Albumin (Human) to a final concentration of 0.1% [1 mL 5% Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP] to prevent adsorption of LEUKINE to the drug delivery system. LEUKINE for intravenous administration must be used immediately after dilution with 0.9 % Sodium Chloride Injection, USP.

Pregnancy

Risk Summary

LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP contain 0.9% benzyl alcohol, which has been associated with gasping syndrome in neonates and infants. The preservative benzyl alcohol can cause serious adverse reactions and death when administered intravenously to neonates and infants. If LEUKINE is needed during pregnancy, reconstitute LEUKINE for injection only with Sterile Water for injection without preservatives [see Dosage and Administration and Use in Specific Populations ].

The limited available data on LEUKINE use in pregnant women are insufficient to inform the drug-associated risk of adverse developmental outcomes. Based on animal studies LEUKINE may cause embryofetal harm. In animal reproduction studies, administration of LEUKINE to pregnant rabbits during organogenesis resulted in adverse developmental outcomes including increased spontaneous abortion at systemic exposures ≥1.3 times the human exposure expected at the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2%-4% and 15%-20%, respectively.

Data

Animal data

In an embryofetal developmental study and a prenatal and postnatal study, pregnant rabbits were administered SC doses of LEUKINE during the period of gestation day (GD) 6 to GD19, GD19 to GD28, or GD19 to parturition at 25, 70, and 200 mcg/kg/day. An increase in spontaneous abortions, late resorptions, and post implantation loss, and a reduction in viable fetuses, mean live litter size, and offspring body weight were evident in rabbits treated with LEUKINE at 200 mcg/kg/day. No adverse effects were observed at ≤70 mcg/kg/day.

After the first administration in rabbits, the dose of 200 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 11-25.3 times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m2; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC in rabbits was reduced to 1.3-5.5 times the clinical exposure by the end of the dosing periods.

Similarly, after the first administration in rabbits, the dose of 70 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 7 to 11 times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m2; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC in rabbits was reduced to 1.0-1.2 times the clinical exposure by the end of the dosing periods.

Lactation

Risk Summary

There is no information regarding the presence of LEUKINE in human milk, the effects on the breastfed child, or the effects on milk production. Administration of LEUKINE to rabbits during lactation resulted in reduction in postnatal offspring survival [see Data]. Because of the potential for serious adverse reactions advise a lactating woman not to breastfeed during treatment and for at least 2 weeks after the last dose.

Data

There are no data regarding the presence of LEUKINE in rabbit milk. However, in the prenatal and postnatal study, lactating rabbits were administered SC doses of LEUKINE during the period of lactation day (LD) 1 to LD14 at 25, 70, and 200 mcg/kg/day. At doses ≥25 mcg/kg/day a reduction in postnatal offspring survival was observed. Maternal toxicity was also observed at LEUKINE doses ≥25 mcg/kg/day.

After the first administration in rabbits, the dose of 25 mcg/kg/day corresponds to a systemic AUC of approximately 2.6 times the exposure observed in patients treated with the clinical LEUKINE dose of 250 mcg/m2 however, due to the production of anti-LEUKINE antibodies with repeat administration, the exposure in rabbits decreased to 0.2 times the clinical exposure by the end of the dosing period.

Pediatric Use

The safety and effectiveness of LEUKINE have been established in pediatric patients 2 years of age and older for autologous peripheral blood progenitor cells and bone marrow transplantation, allogeneic bone marrow transplantation, and treatment of delayed neutrophil recovery or graft failure. Use of LEUKINE for these indications in this age group is based on adequate and well-controlled studies of LEUKINE in adults, in addition to clinical data in 12, 23, and 37 pediatric patients, respectively [See Clinical Studies ]. The pediatric adverse reactions were consistent with those reported in the adult population.

The safety and effectiveness of LEUKINE for pediatric patients less than 2 years of age for autologous peripheral blood progenitor cells and bone marrow transplantation, allogeneic bone marrow transplantation, and treatment of delayed neutrophil recovery or graft failure have not been established.

The use of LEUKINE to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation (H-ARS) is based on efficacy studies conducted in animals and clinical data supporting the use of LEUKINE in patients undergoing autologous or allogeneic BMT following myelosuppressive chemotherapy with or without total body irradiation. Efficacy studies of LEUKINE could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Modeling and simulation were used to derive dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 7 mcg/kg [see Clinical Pharmacology ]. The dose for pediatric patients is based on weight [see Dosage and Administration ].

Safety and effectiveness in pediatric patients have not been established in:

• Acute Myeloid Leukemia: Neutrophil Recovery Following Induction Chemotherapy
• Autologous Peripheral Blood Progenitor Cell Mobilization and Collection

Avoid administration of solutions containing benzyl alcohol [LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol)] to neonates and low birth weight infants. Instead, administer lyophilized LEUKINE reconstituted with Sterile Water for Injection, USP [see Dosage and Administration ].

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.38 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

If LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) must be used in neonates and low birth weight infants, consider the combined daily metabolic load of benzyl alcohol from all sources including LEUKINE (LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP [0.9% benzyl alcohol] contains 9 mg of benzyl alcohol per mL). The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Dosage and Administration ].

Geriatric Use

Clinical studies of LEUKINE did not include a sufficient numbers of subject aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. Parenteral administration of LEUKINE should be attended by appropriate precautions in case an allergic or untoward reaction occurs. If any serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy and institute medical management. Discontinue LEUKINE permanently for patients with serious allergic reactions.

Infusion Related Reactions

LEUKINE can cause infusion-related reactions. Infusion-related reactions may be characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia 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.

Observe closely during infusion for symptoms, particularly in patients with pre-existing lung disease. If patients display dyspnea or other acute symptoms, reduce the rate of infusion by 50%. If symptoms persist or worsen despite rate reduction, discontinue the LEUKINE infusion. If patient experiences infusion-related reaction, subsequent intravenous infusions may be administered following the standard dose schedule with careful monitoring.

Risk of Severe Myelosuppression when LEUKINE Administered within 24 hours of Chemotherapy or Radiotherapy

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy. 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 reactions, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.

Effusions and Capillary Leak Syndrome

Edema, capillary leak syndrome, and pleural and/or pericardial effusion, have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE 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, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure. Body weight and hydration status should be carefully monitored during LEUKINE administration.

Supraventricular Arrhythmias

Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. These arrhythmias have been reversible after discontinuation of LEUKINE. Use LEUKINE with caution in patients with preexisting cardiac disease.

Leukocytosis

White blood cell counts of ≥ 50,000/mm3 were observed in patients receiving LEUKINE. Monitor complete blood counts (CBC) with differential twice per week. Base the decision whether to reduce the dose or interrupt treatment on the clinical condition of the patient [see Dosage and Administration ]. Following cessation of LEUKINE therapy, excessive blood counts have returned to normal or baseline levels within 3 to 7 days.

Potential Effect on Malignant Cells

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.

Discontinue LEUKINE therapy if disease progression is detected during LEUKINE treatment.

Immunogenicity

Treatment with LEUKINE may induce neutralizing anti-drug antibodies. The incidence of anti-sargramostim neutralizing antibodies may be related to duration of exposure to LEUKINE. In a study of patients with normal neutrophil count and a solid tumor in complete response (an unapproved use) treated with LEUKINE for up to 12 months, 82.9% of 41 evaluable patients developed anti-sargramostim neutralizing antibodies and the myelostimulatory effect of LEUKINE was not sustained by day 155 as assessed by WBC count. Use LEUKINE for the shortest duration required [see Adverse Reactions ].

Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol). The “gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

Avoid administration of solutions containing benzyl alcohol (including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP [0.9% benzyl alcohol]) to neonates and low birth weight infants. Instead, administer lyophilized LEUKINE reconstituted with Sterile Water for Injection, USP [see Dosage and Administration ].

If LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) must be used in neonates and low birth weight infants, consider the combined daily metabolic load of benzyl alcohol from all sources including LEUKINE (LEUKINE for injection reconstituted with Bacteriostatic Water contains 9 mg of benzyl alcohol per mL). The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations and Dosage and Administration ].