Eflapegrastim-xnst is a leukocyte growth factor that binds to cell surface receptors on hematopoietic cells stimulating proliferation, differentiation, commitment, and end cell functional activation. It is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Eflapegrastim is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem-cell transplantation. Acute respiratory distress syndrome, fatal splenic rupture, and glomerulonephritis may occur with eflapegrastim.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Subcutaneous Administration
-Eflapegrastim is available as a single-use 13.2 mg/0.6 mL prefilled syringe.
-Do not administer eflapegrastim from 14 days before to 24 hours after administration of cytotoxic chemotherapy.
-Store prefilled syringes in the refrigerator between 36 and 46 degrees F (2 to 8 degrees C) in the carton to protect from light; do not shake and do not use if the syringe is dropped onto a hard surface.
-Allow the prefilled syringe to reach room temperature for a minimum of 30 minutes before administering; discard syringes kept at room temperature longer than 12 hours.
-Do not freeze the eflapegrastim prefilled syringe; discard syringe if frozen.
Subcutaneous Injection:
-Administer eflapegrastim subcutaneously; give the entire contents of the prefilled syringe.
-If a dose is missed, instruct the patient or caregiver to contact their health care provider.
Fatigue was reported in 58% of patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Nausea (52%), diarrhea (40%), decreased appetite/anorexia (19%), and abdominal pain (17%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Headache (29%) and dizziness (16%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Fever was reported in 28% of patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Leukocytosis (white blood cell (WBC) count greater than 100 X 109 cells/L) and thrombocytopenia have been reported in patients who received other recombinant human granulocyte colony-stimulating factor products. Monitor complete blood counts during eflapegrastim therapy. Discontinue eflapegrastim in patients who develop a WBC count greater than 100 X 109 cells/L. Anemia (25%) and thrombocytopenia (14%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Serious allergic reactions (e.g., anaphylactoid reactions) have been reported in patients who received other recombinant human granulocyte colony-stimulating factor products. Permanently discontinue eflapegrastim in patients who experience a serious allergic reaction. Rash (25%) and local administration reaction/injection site reaction (11%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies. Additionally, 3 patients permanently discontinued eflapegrastim therapy due to rash.
Bone pain (38%), myalgia (22%), arthralgia (21%), back pain (20%), pain (12%), and extremity pain (11%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Peripheral edema was reported in 18% of patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Dyspnea (16%) and cough (15%) occurred in patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Flushing was reported in 10% of patients with early-stage breast cancer who received subcutaneous eflapegrastim (n = 314) on day 2 following chemotherapy in a pooled analysis that evaluated adverse reactions through week 14 from 2 randomized studies.
Acute respiratory distress syndrome (ARDS) has been reported in patients who received other recombinant human granulocyte colony-stimulating factor products. Evaluate patients who have signs (e.g., lung infiltrates) or who develop symptoms (e.g., fever, respiratory distress) of ARDS. Discontinue eflapegrastim if a patient is diagnosed with ARDS.
Splenic rupture has been reported in patients who received other recombinant human granulocyte colony-stimulating factor products; some cases of splenic rupture resulted in death. Evaluate patients who have left upper abdominal or shoulder pain after receiving eflapegrastim for evidence of splenomegaly or splenic rupture.
Sickle-cell crisis has been reported in patients with sickle cell disease who received other recombinant human granulocyte colony-stimulating factor products; some cases were fatal. Monitor patients with sickle cell disease for symptoms of a sickle-cell crisis such as pain or difficulty breathing. Discontinue eflapegrastim if sickle-cell crisis occurs.
Glomerulonephritis has been reported in patients who received other recombinant human granulocyte colony-stimulating factor products. Signs of glomerulonephritis include azotemia, hematuria, and proteinuria; a renal biopsy may confirm the diagnosis. Consider holding a dose or a dose reduction if a patient develops glomerulonephritis caused by eflapegrastim.
Capillary leak syndrome has been reported in patients who received other recombinant human granulocyte colony-stimulating factor products. Signs of capillary leak syndrome include hypotension, hypoalbuminemia, hemoconcentration, and edema. Closely monitor and promptly treat patients who develop signs or symptoms of capillary leak syndrome after receiving eflapegrastim; treatment in an intensive care setting may be required.
New primary malignancy including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been reported in patients with lung or breast cancer who received other recombinant human granulocyte colony-stimulating factor products in conjunction with chemotherapy and/or radiotherapy. Monitor these patients during eflapegrastim therapy for signs and symptoms of MDS and AML.
Aortitis has been reported in patients who received other recombinant human granulocyte colony-stimulating factor products; this adverse event may occur in the first week of therapy. Signs and symptoms of aortitis may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., C-reactive protein and white blood cell count). Discontinue eflapegrastim if aortitis is suspected.
In 2 clinical trials (n = 297), antibody formation to eflapegrastim (evaluated using an ELISA assay that had a sensitivity of 65 ng/mL) was detected in 7.1% of patients during the 12-week treatment period and 9.4% of patients at a 12-month follow-up visit. Neutralizing antibodies (evaluated using a cell-based assay with a sensitivity of 1.95 micrograms/mL) developed in 1 patient (0.3%). Treatment-emergent anti-PEG antibodies were detected in 47% of 268 evaluated patients who received eflapegrastim.
Eflapegrastim is contraindicated for use in patients with a history of serious allergic reactions to eflapegrastim or pegfilgrastim or filgrastim products. Eflapegrastim is derived from recombinant E. coli; therefore, use eflapegrastim with caution in patients with a history of E. coli protein hypersensitivity. Serious allergic reactions (e.g., anaphylaxis) may occur with recombinant human granulocyte colony-stimulating factors, such as eflapegrastim. Permanently discontinue eflapegrastim in patients who experience a serious allergic reaction.
Use eflapegrastim with caution in patients with sickle cell disease or sickle cell trait because severe sickle cell crises have been reported in this patient population with use of recombinant human granulocyte colony-stimulating factors, such as eflapegrastim; some cases were fatal. Discontinue eflapegrastim if sickle cell crisis occurs.
Eflapegrastim stimulates the production of hematopoietic stem cells and may act as a growth factor for myeloid cells in myeloid malignancies and myelodysplasia. Additionally, increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Patients with lung cancer or breast cancer who received recombinant human granulocyte colony-stimulating factors in conjunction with chemotherapy and/or radiotherapy may be at increased risk for developing a new primary malignancy including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); monitor these patients for signs and symptoms of MDS and AML.
Leukocytosis (white blood cell [WBC] count greater than 100 X 109 cells/L) and thrombocytopenia have been reported with use of recombinant human granulocyte colony-stimulating factors, such as eflapegrastim. Monitor complete blood counts during therapy. Discontinue eflapegrastim in patients who develop a WBC count greater than 100 X 109 cells/L.
There are no data regarding the use of eflapegrastim during pregnancy. However, data from published studies in other recombinant human granulocyte colony-stimulating factors have not found a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In pregnant rabbits, an increased rate of embryo-fetal death and reduced fetal weight occurred following eflapegrastim doses that resulted in maternal exposures of about 6-times the recommended human dose. No maternal or fetal developmental toxicity was observed in rats eflapegrastim doses that resulted in maternal exposures of up to 7-times the recommended human dose.
Weigh the potential risk to the infant or child against the potential benefits to the mother prior to initiating eflapegrastim therapy in a patient who is breast-feeding. It is not known if eflapegrastim is secreted in human milk or if it has effects on the breast-fed infant or milk production. Endogenous and other recombinant human granulocyte colony-stimulating factors are present in human milk but are not orally absorbed by infants.
For chemotherapy-induced neutropenia prophylaxis, to decrease the incidence of febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia:
Subcutaneous dosage:
Adults: 13.2 mg subcutaneously once per chemotherapy cycle; administer at approximately 24 hours after the completion of cytotoxic chemotherapy. Do not administer eflapegrastim from 14 days before to 24 hours after administration of cytotoxic chemotherapy. Non-inferiority for the duration of severe neutropenia was established with eflapegrastim compared with pegfilgrastim following cytotoxic chemotherapy in patients with early-stage breast cancer in 2 randomized, phase 3 trials. The mean duration of severe (grade 4) neutropenia in cycle 1 (primary endpoint) with eflapegrastim 13.2 mg was non-inferior to pegfilgrastim 6 mg (0.2 +/- 0.503 days vs. 0.35 +/- 0.683 days; difference, -0.148 days; 95% CI, -0.264 to 0.032; p less than 0.0001) following 4 cycles of standard docetaxel plus cyclophosphamide (TC) chemotherapy in patient with early breast cancer in a randomized (1:1), phase 3 (ADVANCE) trial (n = 406). The non-inferiority of eflapegrastim was maintained following chemotherapy cycles 2, 3, and 4. The incidence of severe neutropenia in cycle 1 was 15.8% in the eflapegrastim arm and 24.3% in the pegfilgrastim arm (p = 0.034). The mean duration of severe (grade 4) neutropenia in cycle 1 (primary endpoint) with eflapegrastim 13.2 mg was non-inferior to pegfilgrastim 6 mg (0.31 +/- 0.69 days vs. 0.39 +/- 0.95 days; difference, -0.074 days; 95% CI, -0.292 to 0.129; p less than 0.0001) following 4 cycles of standard TC chemotherapy in patient with early breast cancer in a randomized (1:1), phase 3 (RECOVER) trial (n = 237). The non-inferiority of eflapegrastim was maintained following chemotherapy cycles 2, 3, and 4. The incidence of severe neutropenia in cycle 1 was 20.3% in the eflapegrastim arm and 23.5% in the pegfilgrastim arm.
Maximum Dosage Limits:
-Adults
13.2 mg subcutaneously.
-Geriatric
13.2 mg subcutaneously.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abemaciclib: (Major) Do not administer abemaciclib for at least 48 hours after the last dose of colony stimulating factors, if required. Hematologic toxicities should also be resolved to grade 2 or less prior to resuming treatment with abemaciclib.
Betibeglogene Autotemcel: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Exagamglogene autotemcel: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after exagamglogene autotemcel infusion.
Lovotibeglogene autotemcel: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Eflapegrastim is a long-acting recombinant human granulocyte colony-stimulating factor (G-CSF) produced by covalent coupling of a human G-CSF analog and a Fc fragment of human immunoglobulin G4 via a single polyethylene glycol linker. It binds to G-CSF receptors on myeloid progenitor cells and neutrophils and triggers signaling pathways that control cell differentiation, proliferation, migration, and survival.
Eflapegrastim is administered subcutaneously. In pharmacokinetics studies in healthy subjects and breast cancer patients, the volume of distribution was 1.44 L and the geometric mean half-life during cycle 1 was 36.4 hours (range, 16.1 to 115 hours). The eflapegrastim clearance decreases with increasing doses following single-dose administration; this may be due to target-mediated clearance by neutrophils. Following repeat doses of eflapegrastim, its clearance increased in cycle 3 compared to cycle 1 which may be related to the subsequent increase in neutrophils. Eflapegrastim appears to be metabolized by endogenous degradation following receptor-mediated internalization by cells with G-CSF receptors. It is not excreted in the urine.
-Route-Specific Pharmacokinetics
Subcutaneous Route
The pharmacokinetic parameters of eflapegrastim were nonlinear and exposure increases were not dose-proportional over the dose range of 45 to 350 mcg/kg in healthy subjects and patients with breast cancer who received subcutaneous eflapegrastim. The median Tmax was 25 hours (range, 6 to 144 hours) in patients with breast cancer following the recommended dosage of eflapegrastim.