Sargramostim

FDA Drug Information • Also known as: Leukine

Brand Names: Leukine
Drug Class: Leukocyte Growth Factor [EPC]
Route: INTRAVENOUS, SUBCUTANEOUS
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Sargramostim is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast ( S. cerevisiae ) expression system. 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 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 differs from human GM-CSF by one amino acid at position 23, where leucine is substituted for arginine. LEUKINE (sargramostim) for injection is supplied as a sterile, preservative-free, white lyophilized powder in a single-dose vial for subcutaneous or intravenous use. Reconstitute each single-dose vial with 1 mL of diluent (i.e., sterile water for injection or bacteriostatic water for injection). After reconstitution each single-dose vial contains 250 mcg/mL sargramostim and the inactive ingredients mannitol (40 mg), sucrose (10 mg), and tromethamine (1.21 mg) per mL with a pH range of 7.1 - 7.7 with a deliverable volume of 1 mL (250 mcg).

What Is Sargramostim Used For?

1 INDICATIONS AND USAGE LEUKINE is a leukocyte growth factor indicated: To shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML). ( 1.1 ) For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients. ( 1.2 ) For the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older. ( 1.3 ) For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older. ( 1.4 ) For treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older. ( 1.5 ) 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]). ( 1.6 ) 1.1 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). 1.2 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. 1.3 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). 1.4 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. 1.5 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. 1.6 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...

Dosage and Administration

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for dosage adjustments and timing of administration ( 2.1 - 2.6 ). AML, Neutrophil recovery following chemotherapy: 250 mcg/m 2 /day administered intravenously over a 4-hour period. ( 2.1 ) Mobilization of peripheral blood progenitor cells: 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneous injection once daily. ( 2.2 ) Post peripheral blood progenitor cell transplantation: 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneous injection once daily. ( 2.3 ) Myeloid reconstitution after autologous or allogeneic BMT: 250 mcg/m 2 /day administered intravenously over a 2-hour period. ( 2.4 ) BMT failure or engraftment delayed: 250 mcg/m 2 /day for 14 days as a 2-hour intravenous infusion. ( 2.5 ) Patients acutely exposed to myelosuppressive doses of radiation, administer once daily as subcutaneous injection: Adults and pediatric patients weighing >40 kg: 7 mcg/kg Pediatric patients 15 kg to 40 kg: 10 mcg/kg Pediatric patients <15 kg: 12 mcg/kg ( 2.6 ) 2.1 Neutrophil Recovery Following Induction Chemotherapy for Acute Myeloid Leukemia The recommended dose is 250 mcg/m 2 /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/mm 3 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/mm 3 : 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/m 2 /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/mm 3 , 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Infusion Related Reactions [see Warnings and Precautions ( 5.2 )] Risk of Severe Myelosuppression when LEUKINE Administered within 24 Hours of Chemotherapy or Radiotherapy [see Warnings and Precautions ( 5.3 )] Effusions and Capillary Leak Syndrome [see Warnings and Precautions ( 5.4 )] Supraventricular Arrhythmias [see Warnings and Precautions ( 5.5 )] Leukocytosis [see Warnings and Precautions ( 5.6 )] Potential Effect on Malignant Cells [see Warnings and Precautions ( 5.7 )] Immunogenicity [see Warnings and Precautions ( 5.8 )] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions ( 5.9 )] The most common adverse reactions (incidence >30%) were ( 6.1 ): In recipients of autologous BMT: fever, nausea, diarrhea, vomiting, mucous membrane disorder, alopecia, asthenia, malaise, anorexia, rash, gastrointestinal disorder and edema. In recipients of allogeneic BMT: diarrhea, fever, nausea, rash, vomiting, stomatitis, anorexia, high glucose, alopecia, abdominal pain, low albumin, headache and hypertension. In patients with AML: fever, liver toxicity, skin reactions, infections, metabolic laboratory abnormalities, nausea, diarrhea, genitourinary abnormalities, pulmonary toxicity, vomiting, neurotoxicity, stomatitis, alopecia and weight loss. To report SUSPECTED ADVERSE REACTIONS, contact Partner Therapeutics, Inc., at 1-888-4RX-LEUKINE or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Autologous Peripheral Blood Progenitor Cell (PBPC) and Bone Marrow Transplantation Studies 301, 302 and 303 enrolled a total of 156 patients after autologous or allogeneic marrow or PBPC transplantation. In these placebo-controlled studies, pediatric and adult patients received once-daily intravenous infusions of LEUKINE 250 mcg/m 2 or placebo for 21 days. In Studies 301, 302, and 303, there was no difference in relapse rate between the LEUKINE and placebo-treated patients. Adverse reactions reported in at least 10% of patients who received intravenous LEUKINE or at a rate that was at least 5% higher than the placebo arm are shown in Table 1 . Table 1: Adverse Reactions after Autologous Marrow or PBPC Transplantation in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm Adverse Reactions by Body System LEUKINE (n=79) % Placebo (n=77) % Adverse Reactions by Body System LEUKINE (n=79) % Placebo (n=77) % Body, General Metabolic, Nutritional Disorder Fever 95 96 Edema 34 35 Mucous membrane disorder 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 Blood and Lymphatic System Nausea 90 96 Blood dyscrasia 25 27 Diarrhea 89 82 Cardiovascular Vascular 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 Nervous System Stomatitis 24 29 CNS disorder 11 16 Liver damage 13 14 Skin and Appendages Alopecia 73 74 Rash 44 38 Additional Clinically Significant Adverse Reactions Occurring in Less than 10% Incidence Investigations : Elevated creatinine, elevated bilirubin, elevate transaminases Allogeneic Bone Marrow Transplantation In the placebo-controlled trial of 109 patients after allogeneic BMT (Study 9002), acute graft-vs-host disease occurred in 55% on the LEUKINE arm and in 59% on the placebo arm. Adverse reactions reported in at least 10% of patients who received IV LEUKINE or at a rate at least 5%...

Drug Interactions

7 DRUG INTERACTIONS Use with caution in patients receiving drugs that may potentiate LEUKINE's myeloproliferative effects, such as lithium and corticosteroids. ( 7.1 ) 7.1 Concomitant Use with Products that Induce Myeloproliferation Avoid the concomitant use of LEUKINE and products that induce myeloproliferation (such as lithium and corticosteroids). Such products may increase the myeloproliferative effects of LEUKINE. Monitor patients receiving both LEUKINE and products that induce myeloproliferation frequently for clinical and laboratory signs of excess myeloproliferative effects.

Contraindications

4 CONTRAINDICATIONS Do not administer LEUKINE to patients with a history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony-stimulating factor such as sargramostim, yeast-derived products, or any component of the product. Anaphylactic reactions have been reported with LEUKINE [see Warnings and Precautions ( 5.1 )] . Do not administer LEUKINE to patients with a history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product. ( 4 )

Pregnancy and Breastfeeding

8.1 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 ( 2.7 ) and Use in Specific Populations ( 8.4 )] . 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...

Overdosage

10 OVERDOSAGE Doses up to 100 mcg/kg/day (4,000 mcg/m 2 /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/mm 3 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied LEUKINE (sargramostim) for injection is a sterile, preservative-free, white lyophilized powder supplied in a carton containing five 250 mcg single-dose vials. (NDC 71837-5843-5). Storage and Handling 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.