LEUKINE Powder for solution for injection Ref.[116018] Active ingredients: Sargramostim

2.1 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 (5.3)].

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%

2.2 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 (14)].

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.

2.3 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 (5.3)].

2.4 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 (5.3)].

Dose Modification

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%

2.5 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%

2.6 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.

2.7 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 (5.3)].
• 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 (5.9)].

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.

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 1 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.

In case of overdosage, discontinue LEUKINE therapy and monitor the patient for WBC increase and respiratory symptoms.

Store LEUKINE vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake. Do not use beyond the expiration date printed on the vial.