Filgrastim is a biosynthetic (recombinant DNA origin) hematopoietic agent (human granulocyte colony-stimulating factor [G-CSF]) that principally affects the proliferation and differentiation of neutrophils within the bone marrow1, 4, 76, 78, 79, 80, 81, 82, 145, 151, 157 and possibly other sites (e.g., spleen).23, 42, 105
Filgrastim and tbo-filgrastim are structurally and pharmacologically similar drugs that contain a related drug substance.1, 145, 151 Tbo-filgrastim was licensed by the US Food and Drug Administration (FDA) through a biologics license application (BLA), not as a biosimilar to filgrastim; at the time of tbo-filgrastim's submission for approval, FDA had not finalized a process for approving biosimilars.151, 153, 154
Filgrastim-sndz, filgrastim-aafi, and filgrastim-ayow are biosimilar to filgrastim (Neupogen®).1, 157, 201, 202 The FDA defines a biosimilar as a biological that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.170, 204 The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies (e.g., human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity assessment, additional comparative clinical studies).204 Therefore, biosimilarity of 2 drugs may be established even when there are formulation or minor structural differences or minor differences in rates of adverse effects between the drugs as long as these differences are not clinically meaningful.204 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biological and the reference biological but does not independently establish safety and effectiveness of the proposed biological.204 In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating that the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alternation or switch.169 Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.169 None of the currently available filgrastim biosimilars have interchangeable data at this time.205
In this monograph, unless otherwise stated, the term “filgrastim products” refers to filgastrim (the reference drug); tbo-filgrastim; filgrastim-sndz, filgrastim-aafi, and filgrastim-ayow (the biosimilars), or all products.
Various filgrastim biosimilars are available.157, 201, 202 Biosimilarity of these products has been demonstrated for the indications described in the table below (See Table 1.) Biosimilarity of the filgrastim products has not been demonstrated for use in patients with acute exposure to myelosuppressive doses of radiation; only the reference product (Neupogen®) is currently indicated for this use.1
FDA-labeled indication | Filgrastim-sndz (Zarxio®) | Filgrastim-aafi (Nivestym®) | Filgrastim-ayow (Releuko®) |
|---|---|---|---|
Chemotherapy-induced neutropenia | X | X | X |
Acute myeloid leukemia | X | X | X |
Bone marrow transplantation | X | X | X |
Autologous peripheral blood progenitor cell collection and therapy | X | X | |
Severe chronic neutropenia | X | X | X |
Tbo-filgrastim is only indicated for use in adult and pediatric patients (≥1 month of age) with non-myeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of febrile neutropenia in order to reduce the duration of severe neutropenia.145
Chemotherapy-induced Neutropenia
Filgrastim, tbo-filgrastim, and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) are used to reduce the incidence of infection, as seen by the presence of febrile neutropenia, in patients with non-myeloid malignancies administered myelosuppressive chemotherapeutic agents associated with a significant incidence of febrile neutropenia.1, 145, 157, 201, 202 Myelosuppression is a major factor contributing to infection, morbidity (including that requiring hospitalization), and mortality in patients with malignancies undergoing chemotherapy and is a major dose-limiting factor in many chemotherapy regimens.4, 43, 48, 75, 77, 102 While filgrastim generally produces a beneficial effect on neutrophil recovery in patients with chemotherapy-induced neutropenia,1, 4, 5, 6, 7, 8, 9, 26, 32, 36, 65, 77, 102 substantial, cost-effective clinical benefit, including possible effects on survival and quality of life, may be more difficult to establish.6, 77, 97, 98, 102, 120
In patients with non-myeloid malignancy undergoing myelosuppressive chemotherapy, prophylactic use of filgrastim generally has ameliorated or occasionally prevented associated neutropenia and has decreased the incidence and/or duration of fever and infectious episodes, the frequency and/or duration of hospitalization, and requirements for anti-infective therapy.1, 4, 7, 8, 16, 24, 77, 95, 102 While additional study is necessary to evaluate whether use of filgrastim therapy in patients with non-myeloid malignancy can enhance the efficacy of myelosuppressive chemotherapy or shorten the duration of chemotherapy needed, the drug's ameliorative effects on neutropenia have decreased the need to withhold courses and/or reduce dosages of chemotherapy in some patients and also have permitted dose intensification.6, 8, 32, 64, 102 However, the magnitude of response may show considerable interindividual variation, in part because of underlying patient differences (e.g., extent of prior radiation therapy and chemotherapy, underlying conditions and patient status, chemotherapy regimen employed).4, 23, 26, 77, 102
Prophylactic filgrastim therapy has been used effectively to accelerate the recovery of neutrophil counts following a variety of myelosuppressive chemotherapy regimens in adults with small cell lung carcinoma.1, 5, 7, 26, 32, 77, 102, 157, 201, 202 In a randomized, placebo-controlled study in patients with small cell lung carcinoma receiving 1-6 courses of chemotherapy with etoposide (120 mg/m2 on days 1-3 of each course), cyclophosphamide (1 g/m2 on day 1 of each course), and doxorubicin (50 mg/m2 on day 1 of each course), the incidence, severity, and duration of severe neutropenia (absolute neutrophil count [ANC] <500 cells/mm3) were lower in patients receiving filgrastim (4-8 mcg/kg [230 mcg/m2] daily given subcutaneously for 4-17 consecutive days starting on day 4 after chemotherapy) compared with those receiving placebo.7, 95 Patients receiving filgrastim had a 57% rate of severe neutropenia whereas patients receiving placebo had a 77% rate;95 the median duration of severe neutropenia in cycle 1 was reduced in patients receiving filgrastim compared with those receiving placebo (2 or 6 days, respectively).179 The mean and median severities of neutropenia (as measured by the ANC nadir) during the first cycle of therapy were 496/mm3 (range: 0-1878 cells/mm3)95 , and 72 cells/mm3 (range: 0-7912 cells/mm3), respectively, in patients receiving filgrastim and 204 cells/mm3 (range: 0-1157 cells/mm3) and 38 cells/mm3 (range: 0-9525 cells/mm3),95 respectively, in those receiving placebo; the ANC nadir occurred at a mean of 10 or 12 days in patients receiving filgrastim or placebo, respectively.179 In addition, patients receiving filgrastim had a lower incidence of infection (event rate 40% vs 76%) and lower overall duration of infection (as manifested by febrile neutropenia), and required fewer episodes of hospitalization and fewer days of IV antibiotic therapy compared with patients receiving placebo;1, 4, 7, 102, 157, 201, 202 no differences in survival or disease progression were evident.7, 102, 179
Prophylactic filgrastim therapy also has been used effectively to accelerate the recovery of neutrophil counts following a variety of chemotherapy regimens (some of which included use of methotrexate, doxorubicin, vinblastine, cisplatin, or melphalan) in adults with other types of malignancies, including advanced pulmonary carcinoma,4, 36, 65, 102 bladder carcinoma,26, 48 transitional cell carcinoma of the urothelium,8, 26, 102 testicular carcinoma,48 prostatic carcinoma,48 breast carcinoma,1, 6, 36, 102 ovarian carcinoma,4, 6, 102 neuroblastoma, and non-Hodgkin lymphoma.1, 4, 14 The drug effectively decreased the severity and duration of severe neutropenia in these patients and decreased the duration of hospitalization and requirements for anti-infective therapy; the drug also may decrease the frequency and severity of mucositis.4, 8, 77, 102 Filgrastim therapy has been used with some success to accelerate neutrophil recovery in children with advanced-stage neuroblastoma receiving chemotherapy.114 When used in these children, the drug has reduced the duration of severe neutropenia and decreased the incidence of hospitalization for fever with neutropenia.114 The drug also has been used effectively to reduce the duration of neutropenia and incidence of febrile neutropenia in a limited number of children 7 months to 15 years of age receiving chemotherapy for various other malignancies (e.g., acute lymphocytic leukemia, Wilms' tumor, lymphoma, rhabdomyosarcoma, Hodgkin disease, CNS tumor).133
Filgrastim has been used in conjunction with empiric anti-infective therapy for the treatment of cancer chemotherapy-induced febrile neutropenia†.129 In one randomized, double-blind, placebo-controlled study in patients with non-myeloid malignancies who developed febrile neutropenia following chemotherapy, filgrastim therapy (initiated within 12 hours of empiric anti-infective therapy) reduced the median duration of severe neutropenia and the time to resolution of febrile neutropenia by 1-2 days compared with use of empiric anti-infective therapy alone.129 However, filgrastim therapy did not have a clinically important impact on the duration of fever or median duration of hospitalization required.129 In a meta-analysis evaluating the use of colony stimulating factors (CSFs) in combination with antibiotics compared with antibiotic use alone for the treatment of chemotherapy-induced neutropenia, duration of hospitalization and time to neutrophil recovery were reduced in patients who received CSFs.174 No improvement in overall survival was seen with the therapeutic use of CSFs.174 It has been recommended that patients who have received prophylactic treatment with CSFs and develop febrile neutropenia should continue receiving the same CSF.172 CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.171 For patients who have not received prophylaxis and develop febrile neutropenia, therapy with CSFs may be considered if certain risk factors that indicate an increased risk of infection-related complications or poor outcomes are present (e.g., patients >65 years of age, sepsis syndrome, ANC <100 cells/mm3, anticipated or prolonged neutropenia [exceeding 10 days], pneumonia, invasive fungal infections or other clinically documented infections, hospitalization, prior episodes of febrile neutropenia).171, 172 ,
Efficacy of tbo-filgrastim was established in a multicenter, randomized study in 348 chemotherapy-naive adults with advanced (high-risk stage II, stage III, or stage IV) breast cancer receiving initial chemotherapy with doxorubicin 60 mg/m2 and docetaxel 75 mg/m2.145, 152 Patients were randomly assigned to receive tbo-filgrastim, placebo, or a filgrastim preparation not available in the US; however, demonstration of efficacy is based only on the comparison between tbo-filgrastim and placebo.145, 152, 153 The study drug was initiated one day after chemotherapy at a dosage of 5 mcg/kg once daily by subcutaneous injection, and continued for at least 5 days up to a maximum of 14 days or until a post-nadir ANC of at least 10,000 cells/mm3 was achieved.145 The mean duration of severe neutropenia in the first chemotherapy cycle (primary efficacy end point) was substantially reduced in patients receiving tbo-filgrastim compared with that in placebo recipients (1.1 and 3.8 days, respectively).145, 152
Studies have found that certain chemotherapeutic agents and regimens, as well as the delivered dose intensity, are important predictors of febrile neutropenia and febrile neutropenia-related hospitalizations.175 Antineoplastic agents such as anthracyclines (e.g., doxorubicin), taxanes (e.g., docetaxel), alkylating agents (e.g., cyclophosphamide), and topoisomerase inhibitors (e.g., etoposide), as well as gemcitabine and vinorelbine, have been associated with myelosuppression.175 In adults receiving chemotherapy for a solid tumor or non-myeloid malignancy, guidelines recommend that CSFs be administered prophylactically when the risk of febrile neutropenia is high (exceeding 20%) and if equally effective treatments that do not require CSF support are unavailable.171, 172, 173 Prophylaxis should be initiated in the first cycle and continued through subsequent cycles of chemotherapy.171 Prophylactic administration of CSFs is recommended for any patient considered at high risk, regardless of whether the treatment is intended to be curative, to prolong survival, or to manage symptoms.172 For patients receiving chemotherapy regimens who have an intermediate risk of febrile neutropenia (10-20%), prophylactic use of CSFs can be considered, especially if the increased risk is due to patient factors (e.g., >65 years of age, coexisting illness) instead of the chemotherapy regimen.172, 173 Guidelines also recommend considering previous cytotoxic or radiation therapy, preexisting tumor-related neutropenia or bone marrow involvement, reduced performance status, reduced nutritional status, advanced cancer, impaired renal or hepatic function, and the presence of open sores when estimating a patient's overall risk of febrile neutropenia.171, 173 Prophylaxis is generally not recommended for patients with a low risk (less than 10%) of febrile neutropenia.172 Secondary prophylaxis with CSFs is recommended in patients who have experienced a neutropenic complication from a previous chemotherapy cycle (for which primary prophylaxis was not received), in whom a reduced chemotherapy dose or treatment delay would compromise disease-free or overall survival or treatment outcomes.171, 172
Acute Myeloid Leukemia - Induction and/or Consolidation Chemotherapy
Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) are used to decrease the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).1, 157, 201, 202
Of note, use of filgrastim in patients with acute leukemia has been considered controversial since results of in vitro studies indicated that certain leukemic cell lines have receptors for granulocyte CSF (G-CSF) and that the survival, proliferation, and differentiation of the cells are supported by CSFs.4, 19, 23, 42, 50, 63, 77 In studies in patients with relapsed or refractory AML or acute lymphocytic (lymphoblastic) leukemia (ALL) or patients with leukemia associated with myelodysplastic syndrome, the period of neutrophil recovery was shorter and the incidence of infectious complications was lower in patients who received filgrastim after induction therapy than in those who did not receive the drug.4, 19 Although there was no evidence that filgrastim accelerated regrowth of leukemic cells, regrowth of leukemic blasts in the bone marrow did occur during filgrastim therapy in a few patients with acute leukemia associated with myelodysplastic syndromes;4, 19 it is unclear whether this regrowth would have occurred even without filgrastim therapy.4 While it has been suggested that filgrastim may be a useful antileukemic agent secondary to its stimulation of leukemic differentiation or of proliferation of malignant leukemic cells, thereby increasing their sensitivity to cancer chemotherapy, it also has been suggested that such stimulation might accelerate the malignancy.42, 77 Therefore, some experts have stated that use of filgrastim in patients with myeloid leukemias should be undertaken with caution.42, 77
A double-blind, multicenter trial of over 500 patients (mean age: 54 years; range: 16-89 years) who had completed a course of standard induction chemotherapy (daunorubicin, cytarabine, and etoposide) for newly diagnosed AML randomized patients to receive either filgrastim (5 mcg/kg daily) or placebo initiated 24 hours after the last dose of chemotherapy.1, 136, 157, 201, 202 Therapy was continued until neutrophil recovery (ANC 1000 cells/mm3 for 3 consecutive days or 10,000 cells/mm3 for 1 day) or for a maximum of 35 days.1, 136 Filgrastim therapy decreased the median time to ANC recovery and the median duration of fever, anti-infective use, and hospitalization as compared with placebo following induction chemotherapy.1, 136 In patients treated with filgrastim, the median time from initiation of chemotherapy to ANC recovery (ANC of at least 500 cells/mm3) was 20 days, as compared to 25 days in patients receiving placebo.136 The median duration of fever was reduced by 1.5 days, and there were reductions in the duration of IV anti-infective use, including systemic antifungal (amphotericin B) therapy, and hospitalization in treated patients.136 During consolidation chemotherapy, patients treated with filgrastim also experienced reductions in the incidence of severe neutropenia, time to neutrophil recovery, incidence and duration of fever, and the durations of IV anti-infective use and hospitalization.1, 136 There were no differences between the filgrastim- and placebo-treated groups in terms of complete remission rate (69 or 68%, respectively), median time to disease progression in all patients randomized (165 or 186 days, respectively), or median overall survival (380 or 425 days, respectively).1 Filgrastim did not appear to affect prognosis of patients with AML.1, 136 Other reports of filgrastim therapy in patients receiving induction or consolidation chemotherapy for AML also showed decreased time to ANC recovery,137, 138, 139 sustained increase in ANC,140 decreased incidence and duration of fever,137, 138 and decreased use of IV anti-infectives;137 the effects of the drug on hospitalization were less clear.137, 138 Filgrastim appeared to have no adverse effects on duration of complete remission or survival.137, 138, 139
Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) are used to decrease the duration of neutropenia and neutropenia-related clinical sequelae in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).1, 157, 201, 202
When used following autologous BMT in adults with various non-myeloid malignancies,4, 16 non-Hodgkin lymphoma,16, 125 Hodgkin disease,4, 16, 24, 32, 125, 126 or ALL,4, 16 filgrastim therapy effectively shortened the duration of severe neutropenia, decreased the median duration of infectious episodes and anti-infective therapy required, and shortened the median duration of hospitalization required.16, 24, 32, 33, 77, 102, 125, 126 Filgrastim therapy also has effectively shortened the duration of severe neutropenia when used in a limited number of adults with myeloid† and non-myeloid malignancies undergoing allogeneic BMT.1, 33, 77
In one randomized, controlled study in patients with non-Hodgkin lymphoma or Hodgkin disease undergoing autologous BMT, the median time to neutrophil recovery (defined as the first of 3 consecutive days when neutrophil counts were ≥500 cells/mm3) was 10 days in patients who received filgrastim therapy (10 or 20 mcg/kg daily by continuous subcutaneous infusion) compared with 18 days in patients who received placebo.125 The median duration of febrile neutropenia was 5 days in those who received filgrastim compared with 13.5 days in those who received placebo.1, 125, 157, 201, 202 When filgrastim therapy was used in a nonrandomized study in patients with non-Hodgkin lymphoma, Hodgkin disease, ALL, or germ cell tumor undergoing autologous BMT, the average time to neutrophil recovery was 11 days.16 In another randomized, controlled trial, patients with non-Hodgkin lymphoma or Hodgkin disease undergoing autologous BMT received filgrastim 10 or 30 mcg/kg daily as a 24-hour continuous IV infusion (starting 24 hours after bone marrow infusion for a maximum of 28 days) or no filgrastim.1, 157, 176, 201, 202 A substantial reduction in the median duration of severe neutropenia (ANC <500 cells/mm3) was demonstrated in patients who received filgrastim therapy compared with that in patients who received no filgrastim (11 and 23 days, respectively).1, 157, 201, 202 In one randomized, placebo-controlled trial in adults with myeloid† and non-myeloid malignancies undergoing allogeneic BMT, the median duration of severe neutropenia and time to neutrophil recovery (ANC ≥500 cells/mm3) were 15 and 16 days, respectively, in patients who received filgrastim (300 mcg/m2 daily) compared with 19 and 21 days, respectively, in patients who received placebo.1, 157, 201, 202
Autologous Peripheral Blood Progenitor Cell Collection and Therapy
Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi) are used for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.1, 157, 201
Use of filgrastim for mobilization of peripheral blood progenitor cells (PBPCs) has been evaluated in several clinical trials in patients with non-Hodgkin lymphoma, Hodgkin disease, ALL, breast cancer, and germ-cell tumor.1, 72, 77, 157, 201 Filgrastim generally was administered for 6-7 days and leukapheresis was performed on days 5, 6, and 7 (except for a limited number of patients who received apheresis on days 4, 6, and 8).1, 72, 157, 201 Filgrastim also was administered to these patients following autologous PBPC transplantation of the filgrastim-mobilized leukapheresis product until a sustainable ANC (≥500 cells/mm3) was attained.1, 157, 201 Engraftment was evaluated in 64 patients who underwent transplantation using filgrastim-mobilized autologous hematopoietic progenitor cells and approximately 3% of these patients did not achieve the criteria for engraftment as defined by a platelet count of at least 20,000 cells/mm3 by 28 days. 1, 157, 201 The rate of engraftment following filgrastim-mobilized PBPC transplantation without filgrastim therapy following the procedure has not been studied.1, 157, 201
In a randomized study in patients with Hodgkin disease or non-Hodgkin lymphoma undergoing myeloablative cancer chemotherapy, autologous transplantation of filgrastim-mobilized PBPCs followed by filgrastim therapy (n=27) was compared with autologous BMT followed by filgrastim therapy (n=31).1, 157, 177, 201 The median time to sustained ANC of ≥500 cells/mm3 was 11 or 14 days in those who received autologous PBPC or autologous BMT, respectively.177 Patients who received autologous PBPC required fewer days of platelet transfusions; the median duration of platelet transfusions after grafting was 6 days in those who received PBPC versus 10 days in those who received autologous BMT.1, 157, 177, 201 In addition, patients who received autologous PBPCs had fewer days of erythrocyte transfusions and a shorter duration of hospitalization.177 While filgrastim therapy may be effective for mobilization of PBPC,1, 72, 77 the optimum schedule for such therapy, the duration of engraftment with PBPC transplantation, and the potential of circulating malignant cells to propagate the malignancy remain to be established.77
Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) are used to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital, cyclic, or idiopathic neutropenia.1, 157, 201, 202 These severe chronic neutropenias are characterized by a selective decrease in the number of circulating neutrophils and an enhanced susceptibility to bacterial infections.178 Therapy in patients with severe chronic neutropenia previously relied principally on supportive care alone.77 While filgrastim can produce sustained amelioration of the underlying neutropenia in certain patients with these conditions,1, 20, 30, 77, 105 neutrophil counts decrease to pretreatment levels shortly after discontinuance of therapy with the drug.4, 20
When used in adults and children 4 months to 19 years of age with severe congenital neutropenia (Kostmann syndrome), cyclic neutropenia, or idiopathic neutropenia, filgrastim therapy has increased neutrophil counts, reduced the incidence and duration of infectious episodes and fever, and reduced the incidence, duration, and severity of oropharyngeal ulcers and requirements for anti-infective therapy in these patients.1, 4, 13, 15, 20, 32, 73, 77, 104, 178 In many patients with cyclic neutropenia, the average neutrophil count is 10-12 times higher during filgrastim therapy and the neutropenic cycle length is shortened from 21 to 14 days;15, 104 this is associated with a reduction in the frequency of infectious episodes and a reduction in the severity of symptoms of infection and inflammation.15 In addition to ameliorating neutropenia, the drug increases the amplitude and frequency of cycling in circulating progenitor cell numbers in these patients, suggesting a stem cell effect.104
Acute Exposure to Myelosuppressive Doses of Radiation
The reference filgrastim product (Neupogen®) is used to improve survival in patients acutely exposed to myelosuppressive radiation doses.1
Due to ethical and feasibility issues, efficacy studies evaluating filgrastim in humans with acute radiation syndrome could not be performed.1 The administration of filgrastim for this indication is based on studies conducted in animals and data from studies supporting the use of filgrastim for other approved indications.1
Myelodysplastic Syndromes and Aplastic Anemia
Filgrastim has been used to increase neutrophil counts in adults with MDS†.28, 29, 32, 35, 37, 55, 57, 61, 75, 77 While filgrastim has shown some promise for this use, safety and efficacy of the drug in the treatment of neutropenia associated with myelodysplastic disorders have not been established1 and use of the drug generally should be limited to experts in such therapy. Filgrastim has effectively increased neutrophil counts in patients with MDS classified as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T).4, 28, 29, 37, 57, 61 However, there appears to be considerable interindividual variation in filgrastim dosage required for the neutrophil response,4, 28, 29, 35 and prolonged maintenance therapy with the drug is necessary since neutrophil counts return to pretreatment levels within 1-4 weeks after filgrastim is discontinued.4, 28, 29, 35, 37, 55, 61 In some patients with MDS, there was a reduced need for red blood cell transfusions during filgrastim therapy;4, 28, 35, 37 no clinically important effects on lymphocyte, monocyte, platelet, or eosinophil counts were apparent.35, 37
Whether use of filgrastim in patients with MDS will alter (either increase or decrease) the rate of progression to acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) or affect the usually fatal outcome of the disease is unclear.4, 35, 37, 77 The rate of progression to AML in untreated patients with MDS is approximately 10-20%, 40-50%, and 60-75% in those with RA, RAEB, and RAEB-T, respectively.55 There is concern, but no clear evidence indicated to date, that use of filgrastim may stimulate progression to AML in patients with MDS since in vitro evidence indicates that the drug can stimulate the growth of myeloid leukemic blast cells and because an increase in the percentage of leukemic blasts in the bone marrow has occurred in some patients with MDS receiving the drug.32, 55, 61
Filgrastim has been used with some success to increase the neutrophil count in a limited number of children 1-17 years of age† with moderate to severe aplastic anemia†.4, 18, 40 However, patients with aplastic anemia generally have variable responses to hematopoietic growth factors, 32, 111 and patients with severe neutropenia (neutrophil counts <300 cells/mm3) may not respond to the drug because of the absence of circulating hematopoietic progenitor cells. 111 Further study is needed to evaluate the use of filgrastim in aplastic anemia and to determine the long-term safety and efficacy of the drug in these patients; 40 pending accumulation of such data, this use generally should be limited to experts in such therapy.
Neutropenia Associated with HIV Infection and Antiretroviral Therapy
Filgrastim has been used in some patients with HIV infections in an effort to correct or minimize HIV-associated neutropenia and/or drug-induced neutropenia†.4, 25, 26, 27, 31, 38, 52, 54, 59, 77, 132 When used in patients with HIV infection, filgrastim has effectively increased neutrophils and monocytes, but has had no clinically important effect on the number of erythrocytes, platelets, lymphocytes, eosinophils, or basophils.59 Some clinicians state that use of filgrastim to increase neutrophil counts in HIV-infected patients in an attempt to reduce the risk of bacterial infections in these patients can be considered. 143 However, more data are needed to fully determine the benefit of filgrastim therapy in neutropenic patients with HIV infection.142, 143
Filgrastim has been effective when used alone or in conjunction with epoetin alfa (a recombinant erythropoietin) in adults with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) to ameliorate the hematologic toxicity (severe anemia and/or granulocytopenia) associated with zidovudine therapy†.4, 25, 59, 77 Epoetin alfa alone has been shown to be effective in ameliorating the anemia but not the granulocytopenia associated with zidovudine therapy.25 In a study in adults with HIV infection and substantial bone marrow suppression, filgrastim therapy was administered initially to increase the neutrophil count and epoetin alfa therapy was then added to increase the hemoglobin concentration after the neutrophil count had normalized; zidovudine therapy was then reinstituted and, in some patients, was given concomitantly with both hematopoietic growth factors.25 While the neutrophil count decreased substantially (compared with the initial filgrastim-induced increase) following initiation of epoetin alfa therapy and again when zidovudine was reinitiated, counts still remained substantially above baseline values during continued filgrastim therapy, and such combined therapy permitted resumption of full-dose zidovudine therapy in many patients who had developed intolerance.25
Filgrastim has been used in a limited number of patients in an attempt to delay or slow progression of ALS†. 180, 182, 183, 184, 185, 186, 187, 188 Results of a few small studies in patients with ALS suggest that G-CSF therapy may delay functional decline; however, other studies have reported no beneficial effects.167, 181, 182, 183, 187 In a randomized, double-blind, placebo-controlled pilot trial in 10 patients with ALS, a reduction in structural disintegration of white matter tracts was observed in ALS patients treated with filgrastim 10 mcg/kg daily subcutaneously on days 1-10 and 20-25.187 No substantial differences were found between treatment groups in clinical tests and brain volumetry from baseline to day 100; however, a reduction in structural disintegration of white matter tracts in patients treated with filgrastim was observed.187
Filgrastim has been used effectively to increase neutrophil counts in a limited number of patients with hairy cell leukemia (leukemic reticuloendotheliosis) complicated by severe neutropenia†.4, 13, 17, 121, 122, 123, 124 The ANC normalized in these patients within 1-2 weeks following initiation of filgrastim therapy (approximately 1-7 mcg/kg given once daily by subcutaneous injection for 2-12 weeks).17, 121, 122 Although it has been suggested that filgrastim may become a useful adjunct to current therapy (e.g., cladribine, interferon alfa, pentostatin) for hairy cell leukemia, further study is needed to more fully evaluate efficacy and safety of filgrastim in these patients.4, 17, 121, 122, 123, 124
Filgrastim has been used effectively in a limited number of patients with nonmalignant conditions† who developed neutropenia while receiving various myelosuppressive drugs.41, 116, 117, 118, 119 The drug has been administered in at least one patient who developed bone marrow toxicity while receiving methotrexate treatment for rheumatoid arthritis.41 The drug also has been used effectively in a few patients for the management of agranulocytosis associated with clozapine,116, 128 methimazole,117, 127 captopril,118 procainamide, gold, phenothiazine, azathioprine, ticlopidine hydrochloride, phenobarbital, phenytoin, ciprofloxacin, cefuroxime, chloramphenicol, or sulfasalazine therapy,127 and for mesalazine-associated neutropenia.119 In addition, filgrastim therapy appeared to accelerate bone marrow recovery in one patient who developed pancytopenia following colchicine overdosage.115
Filgrastim therapy also has been used effectively to increase the neutrophil count in a few children 19 months to 21 years of age with glycogen storage disease type Ib†.53, 71 Filgrastim has been administered to at least one 3-month-old child for the treatment of neutropenia associated with sepsis†.51
Dispensing and Administration Precautions
Depending on the product and indication for use, filgrastim may be administered by subcutaneous injection, short IV infusion (15 to 30 minutes), or continuous IV infusion.1, 145, 157, 201, 202 Filgrastim has also been administered by continuous subcutaneous infusion†.9, 16, 72 When administered by continuous subcutaneous infusion for chemotherapy-induced neutropenia or bone marrow transplantation (BMT), filgrastim has been infused over 24 hours.4, 9, 16, 72, 92, 125 For extended IV or subcutaneous infusions, a controlled-infusion device generally is employed.6, 9, 16, 72, 92
Subcutaneous injection is the most convenient for self-administration of the filgrastim products4, 7, 13, 15, 17, 35, 48, 76, 102 and is especially useful when prolonged maintenance therapy with the drug is necessary.4, 6, 13, 15, 17, 28, 42, 102 Recommended sites for subcutaneous injection of filgrastim, tbo-filgrastim, or biosimilars include the outer area of the upper arms, abdomen (except for the 2-inch area around the navel), thighs, and the upper outer areas of the buttocks.1, 145, 157 201, 202 Injection sites should be rotated daily; any area that is tender, red, bruised, scaly, hard, or has stretch marks or scars should be avoided.1, 145, 157, 201, 202
If a filgrastim product is administered by a patient or caregiver and a dose is missed, the patient or caregiver should contact their healthcare provider.1, 145, 157, 201, 202
Discard any unused portion of filgastrim product in vials or prefilled syringes.1, 145, 157, 201, 202 Do not re-enter the vial and do not save unused filgrastim product for administration at a later date.1, 145, 157, 201, 202
Visually inspect any filgrastim products for particulate matter and discoloration prior to administration.1, 145, 157, 201, 202 Do not administer filgrastim products if particulate matter or discoloration is observed.1, 145, 157, 201, 202 Avoid shaking filgrastim products.1, 145, 157, 201, 202 Transport of filgrastim via a pneumatic tube system has not been evaluated.1, 201
Filgrastim is supplied in single-dose prefilled syringes (for subcutaneous use) and single-dose vials (for both subcutaneous use and IV infusion).1 Store the prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.1 Prior to administration, remove from refrigeration and allow to reach room temperature for at least 30 minutes and no more than 24 hours.1 Avoid freezing; however, if frozen, thaw in the refrigerator prior to administration.1 Discard any prefilled syringe or vial frozen more than once or left at room temperature for >24 hours.1
If IV administration is required, dilute filgrastim (vial only) in 5% Dextrose from a concentration of 300 mcg/mL to 5 mcg/mL.1 Do not dilute to <5 mcg/mL.1 Protect filgrastim, diluted to concentrations from 5 to 15 mcg/mL, from adsorption to plastic by adding Albumin (Human) to a final concentration of 2 mg/mL.1 Filgrastim diluted in 5% Dextrose or 5% Dextrose plus Albumin (Human) is compatible with glass bottles, polyvinyl chloride and polyolefin IV bags, and polypropylene syringes.1 Do not dilute with saline as precipitation may occur.1 Store the diluted solution at room temperature for up to 24 hours, which includes time during storage and the duration of the infusion.1
For continuous subcutaneous infusion†, filgrastim has been diluted in 10-50 mL of 5% dextrose injection and infused subcutaneously at a rate not exceeding 10 mL/24 hours.9
Tbo-filgrastim is supplied in single-dose prefilled syringes and vials for subcutaneous use.145 Store the prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.145 Tbo-filgrastim may be removed from refrigeration for a single period of up to 5 days between 23° to 27°C and returned to refrigeration, up to the product expiration date, if not used during the 5 day period.145 Exposure to -1° to -5°C for up to 72 hours and temperatures as low as -15° to -25°C for up to 24 hours do not adversely affect the stability of tbo-filgrastim.145
Filgrastim biosimilars (Zarxio®; Nivestym®; Releuko®)
The filgrastim biosimilars are supplied in single-dose prefilled syringes (Zarxio®; Nivestym®; Releuko®) for subcutaneous use and single-dose vials (Nivestym®; Releuko®) for subcutaneous or IV use.157, 201, 202 Store the prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.157, 201, 202
Prior to administration, remove the Zarxio® prefilled syringe from refrigeration and allow to reach room temperature for at least 30 minutes and for a maximum of 4 days.157 Avoid freezing; however, if frozen, thaw in the refrigerator prior to administration.157 Discard any prefilled syringe frozen more than once or left at room temperature for >4 days.157
Prior to administration, remove the Nivestym® and Releuko® prefilled syringe or vial from refrigeration and allow to reach room temperature for at least 30 minutes and no more than 24 hours.201, 202 Avoid freezing; however, if Nivestym® is frozen, thaw in the refrigerator prior to administration.201 Do not freeze Releuko®.202 Discard any prefilled syringe or vial frozen more than once or left at room temperature for >24 hours.201, 202
If IV administration is required, dilute Nivestym® and Releuko® (vial only) in 5% Dextrose from a concentration of 300 mcg/mL to 5 mcg/mL.201, 202 Do not dilute to <5 mcg/mL.201, 202 Protect these biosimilars, diluted to concentrations from 5 to 15 mcg/mL, from adsorption to plastic by adding Albumin (Human) to a final concentration of 2 mg/mL.201, 202 Nivestym® and Releuko® diluted in 5% Dextrose or 5% Dextrose plus Albumin (Human) are compatible with glass bottles, polyvinyl chloride, and polyolefin IV bags, and polypropylene syringes.201, 202 Do not dilute with saline as precipitation may occur.201, 202 Store the diluted solution at room temperature for up to 24 hours (Nivesytm®) or up to 4 hours (Releuko®), which includes time during storage and the duration of the infusion.201, 202
Chemotherapy-induced Neutropenia
The recommended initial dosage of filgrastim and the approved biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) is 5 mcg/kg/day given as a single daily subcutaneous injection, short IV infusion (15 to 30 minutes), or continuous IV infusion.1, 157, 201, 202 Consider dose increases in increments of 5 mcg/kg for each chemotherapy cycle, based on the duration and severity of the absolute neutrophil count (ANC) nadir.1, 157, 201, 202
The recommended dose of tbo-filgrastim is 5 mcg/kg/day given as a subcutaneous injection.145 Tbo-filgrastim is specifically labelled only for use in adults and pediatric patients ≥1 month of age.145 The product labeling for filgrastim and the biosimilars do not contain similar language for this approved indication.1, 157, 201, 202
Obtain a complete blood count (CBC) and platelet count at baseline and monitor twice weekly during therapy.1, 145, 157, 201, 202
Administer at least 24 hours after cytotoxic chemotherapy; do not give within the 24-hour period prior to chemotherapy.1, 145, 157, 201, 202
One to 2 days after filgrastim therapy initiation, a transient increase in neutrophil count is typically observed.1, 157, 201, 202 In order to ensure a sustained response to therapy, administer for up to 2 weeks or until the ANC has reached 10,000 cells/mm3 following the expected chemotherapy-induced nadir.1, 157, 201, 202 Duration of therapy may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.1, 157, 201, 202
Acute Myeloid Leukemia - Induction and/or Consolidation Chemotherapy
The recommended initial dosage of filgrastim or biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) is 5 mcg/kg/day given as a single daily subcutaneous injection, short IV infusion (15 to 30 minutes), or continuous IV infusion.1, 157, 201, 202 Consider dose increases in increments of 5 mcg/kg for each chemotherapy cycle, based on the duration and severity of the ANC nadir.1, 157, 201, 202
Obtain a CBC and platelet count at baseline and monitor twice weekly during therapy.1, 157, 201, 202
Administer at least 24 hours after cytotoxic chemotherapy; do not give within the 24-hour period prior to chemotherapy.1, 157, 201, 202
One to 2 days after filgrastim therapy initiation, a transient increase in neutrophil count is typically observed.1, 157, 201, 202 In order to ensure a sustained response to therapy, give filgrastim for up to 2 weeks or until the ANC has reached 10,000 cells/mm3 following the expected chemotherapy-induced nadir.1, 157, 201, 202 Duration of therapy may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.1, 157, 201, 202
The recommended dosage of filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) is 10 mcg/kg/day given as an IV infusion for no longer than 24 hours.1, 157, 201, 202 Give the initial dose at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.1, 157, 201, 202
Monitor platelet counts and CBCs frequently after bone marrow transplantation.1, 157, 201, 202
During neutrophil recovery, titrate the filgrastim or biosimilar daily dosage against the neutrophil response (See Table 2).1, 157, 201, 202
Absolute Neutrophil Count | Dosage Adjustment |
|---|---|
When ANC >1000 cells/mm3 for 3 consecutive days | Decrease to 5 mcg/kg/daya |
Then, if ANC remains >1000 cells/mm3 for 3 more consecutive days | Discontinue therapy |
Then, if ANC decreases to <1000 cells/mm3 | Reinitiate therapy at 5 mcg/kg/day |
aIf ANC reduces to <1000 cells/mm3 at any time while the patient is receiving 5 mcg/kg/day, increase the dosage to 10 mcg/kg/day, and then follow the steps in Table 2.
Autologous Peripheral Blood Progenitor Cell Collection and Therapy
The recommended dosage of filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi) is 10 mcg/kg/day given by subcutaneous injection.1, 157, 201 Give for at least 4 days before the initial leukapheresis procedure and continue until the last procedure.1, 157, 201 Optimal duration of filgrastim administration and leukapheresis schedule not established; however, filgrastim administration for 6 to 7 days with leukaphereses on days 5, 6, and 7 has been found to be effective and safe.1, 157, 201
Monitor neutrophil counts after 4 days of filgrastim and discontinue therapy if white blood cell count rises to >100,000 cells/mm3.1, 157, 201
The recommended initial dosage of filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) in patients with congenital neutropenia is 6 mcg/kg as a subcutaneous injection given twice daily.1, 157, 201, 202
The recommended initial dosage of filgrastim or biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow) in patients with idiopathic or cyclic neutropenia is 5 mcg/kg as a subcutaneous injection given once daily.1, 157, 201, 202
Chronic daily therapy is required for maintenance of benefit.1, 157, 201, 202 Dosage may be individualized based on ANC and clinical course of the patient.1, 157, 201, 202 Results from a postmarketing study revealed that lower median daily dosages of filgrastim were necessary for patients with idiopathic (1.2 mcg/kg) and cyclic (2.1 mcg/kg) neutropenia as compared to congenital (6 mcg/kg) neutropenia.1, 157, 201, 202 Rarely, patients with congenital neutropenia may require filgrastim dosages ≥100 mcg/kg/day.1, 157, 201, 202
Monitor CBCs with differential and platelet counts during the initial 4 weeks of therapy, during the 2 weeks following any dosage adjustment, and monthly during the first year of treatment once the patient is clinically stable.1, 157, 201, 202 If the patient remains clinically stable after the initial year of treatment, less frequent routine monitoring is recommended.1, 157, 201, 202
Acute Exposure to Myelosuppressive Doses of Radiation
The recommended subcutaneous dosage of filgrastim (Neupogen®) is 10 mcg/kg as a single daily subcutaneous injection.1 Give the dose as soon as possible after suspected or confirmed exposure to radiation doses >2 gray.1 Continue therapy until the ANC is >1000 cells/mm3 for 3 consecutive CBCs or exceeds 10,000 cells/mm3 after a radiation-induced nadir.1
Obtain a baseline CBC and subsequent serial CBCs approximately every third day until the ANC is >1000 cells/mm3 for 3 consecutive CBCs.1 Do not delay therapy if a CBC is not readily available.1
Estimate the level of radiation exposure via clinical findings (e.g., time to vomiting onset, lymphocyte depletion kinetics), biodosimetry (if available), and information from public health authorities.1
The manufacturers of filgrastim and the biosimilars state that dosage adjustment in patients with hepatic impairment is not necessary.1, 157, 201, 202 The manufacturer of tbo-filgrastim makes no specific dosage recommendations for patients with hepatic impairment.145
The manufacturers of filgrastim and the biosimilars state that dosage adjustment in patients with renal impairment is not necessary.1, 157, 201, 202 The manufacturer of tbo-filgrastim makes no specific dosage recommendations for patients with renal impairment.145
The manufacturers of filgrastim products make no specific dosage recommendations for geriatric patients.1, 145, 157, 201, 202
Splenic rupture, including fatal cases, has been reported with therapy.1, 145, 157, 201, 202 Monitor patients for left upper abdominal pain or shoulder pain as these symptoms may be suggestive of an enlarged spleen or splenic rupture.1, 145, 157, 201, 202
Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) has been reported with therapy.1, 145, 157, 201, 202 Monitor patients for the development of fever and lung infiltrates or respiratory distress as these signs and symptoms may be suggestive of ARDS.1, 145, 157, 201, 202 Discontinue filgrastim products in patients with ARDS.1, 145, 157, 201, 202
Serious allergic reactions, including anaphylaxis, have been reported with therapy.1, 145, 157, 201, 202 Most of these reactions occur upon initial exposure to filgrastim products.1, 145, 157, 201, 202 Serious allergic reactions, including anaphylaxis, can recur within days after discontinuing treatment for the initial reaction.1, 157, 201, 202 Permanently discontinue filgrastim products in patients with serious allergic reactions.1, 145, 157, 201, 202 Do not administer filgrastim products to patients with a history of serious allergic reactions to these products or pegfilgrastim.1, 145, 157, 201, 202
Severe sickle cell crises, including fatal cases, have been reported in patients with sickle cell disorders administered filgrastim products.1, 145, 157, 201, 202 Discontinue therapy if a sickle cell crisis occurs.1, 145, 157, 201, 202
Glomerulonephritis has been reported with therapy.1, 145, 157, 201, 202 If glomerulonephritis is suspected, assess for the underlying etiology.1, 145, 157, 201, 202 If a filgrastim product is the likely cause, consider reducing the dose or interrupting therapy.1, 145, 157, 201, 202
In patients with cancer receiving chemotherapy, WBC counts ≥100,000 cells/mm3 were seen in an estimated 2% of patients administered filgrastim at dosages >5 mcg/kg/day and in less than 1% of patients receiving tbo-filgrastim.1, 145, 157, 201, 202 To avoid risks associated with leukocytosis, filgrastim therapy should be discontinued in these patients if ANC >10,000 cells/mm3 after the chemotherapy-induced ANC nadir occurs.1, 145, 157, 201, 202 Monitor CBCs at least twice weekly during therapy.1, 145, 157, 201, 202 Filgrastim dosages that increase the ANC >10,000 cells/mm3 may not result in additional clinical benefit.1, 145, 157, 201, 202 Discontinuation of filgrastim in these patients usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to baseline in 1 to 7 days.1, 145, 157, 201, 202
For patients with cancer undergoing peripheral blood progenitor cell (PBPC) mobilization receiving filgrastim products, discontinue filgrastim if the leukocyte count increases to >100,000 cells/mm3.1, 145, 157, 201, 202
Thrombocytopenia has been reported with therapy.1, 145, 157, 201, 202 Monitor platelet counts.1, 145, 157, 201, 202
Symptoms of capillary leak syndrome (e.g., hypotension, hypoalbuminemia, edema, hemoconcentration) may occur with therapy.1, 145, 157, 201, 202 The syndrome may be life-threatening if treatment is delayed.1, 145, 157, 201, 202 Closely monitor patients who develop capillary leak syndrome and initiate symptomatic treatment.1, 145, 157, 201, 202
Tumor Growth Stimulatory Effects
Filgrastim products may potentially act as growth factors for any tumor type.1, 145, 157, 201, 202 The safety of filgrastim products in the setting of chronic myeloid leukemia (CML) and myelodysplasia specifically has not been established.1, 145, 157, 201, 202
When filgrastim products are used to mobilize PBPC, tumor cells may be collected in the leukapheresis product and subsequently reinfused.1, 157, 201 The effects of reinfusion of tumor cells have not been well studied and available data are inconclusive.1, 157, 201
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Patients with breast and lung cancer who receive filgrastim products in conjunction with chemotherapy and/or radiotherapy may potentially develop MDS and AML.1, 157, 201, 202 Monitor these patients for signs and symptoms of MDS/AML.1, 157, 201, 202
For patients with severe chronic neutropenia, confirm the diagnosis prior to administering filgrastim products.1, 157, 201, 202 Both MDS and AML have occurred in the natural history of congenital neutropenia without cytokine therapy.1, 157, 201, 202 Patients with severe chronic neutropenia who are treated with filgrastim products have experienced cytogenetic abnormalities, MDS transformation, and AML.1, 157, 201, 202 The risk of MDS and AML development appears to be confined to the subset of patients with congenital neutropenia.1, 157, 201, 202 It is unknown what effect filgrastim products have on the development of abnormal cytogenetics and the effect that continued administration has in patients with abnormal cytogenetics or MDS.1, 157, 201, 202 Monitor for signs and symptoms of MDS/AML in these settings.1, 157, 201, 202 Consider the risks and benefits of continued filgrastim therapy in patients with severe chronic neutropenia who develop abnormal cytogenetics or myelodysplasia.1, 157, 201, 202
Signs and symptoms of aortitis (e.g., fever, abdominal pain, malaise, back pain, and increased inflammatory markers) have been reported with therapy and may occur as soon as the initial week of treatment.1, 145, 157, 201, 202 Discontinue filgrastim products if aortitis is suspected.1, 145, 157, 201, 202
Transient positive bone imaging changes may occur due to the increased hematopoietic bone marrow activity observed with growth factor therapy.1, 145, 157, 201, 202 These changes should be taken into consideration when interpreting bone imaging results.1, 145, 157, 201, 202
Alveolar Hemorrhage and Hemoptysis
Alveolar hemorrhage, presenting as pulmonary infiltrates, and hemoptysis necessitating hospitalization have been reported with therapy in patients undergoing PBPC collection mobilization.1, 145, 157, 201, 202 Discontinuation of filgrastim products resulted in hemoptysis resolution.1, 145, 157, 201, 202 Use of filgrastim products for PBPC mobilization in healthy donors is not an approved use.1, 145, 157, 201, 202
Cutaneous vasculitis has been reported with therapy, with severity ranging from moderate to severe.1, 157, 201, 202 The majority of patients with cutaneous vasculitis were administered long-term filgrastim therapy for severe chronic neutropenia.1, 157, 201, 202 If cutaneous vasculitis occurs, hold filgrastim therapy.1, 157, 201, 202 When symptom resolution occurs and the ANC decreases, filgrastim may be reinitiated at a reduced dosage.1, 157, 201, 202
Simultaneous Use with Chemotherapy and Radiation Therapy
Safety and efficacy of filgrastim products administered simultaneously with cytotoxic chemotherapy and/or radiotherapy have not been established.1, 145, 157, 201, 202 Avoid simultaneous use of filgrastim products with chemotherapy and radiotherapy.1, 145, 157, 201, 202
Do not use filgrastim products in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy.1, 145, 157, 201, 202
Anti-drug antibodies have been detected with filgrastim use, with available data suggesting that a small proportion of patients develop binding antibodies.1, 157, 201, 202 In studies, the incidence of antibodies binding to filgrastim was 11 (3%) of 333 patients.1, 157, 201, 202 No evidence of a neutralizing response was seen in these patients.1, 157, 201, 202 For tbo-filgrastim, anti-drug antibodies occurred in 1.4% of 486 patients in a study.145 None of these patients had cross-reactive antibodies to native G-CSF and all antibody responses were transient and of low titers.145
Clinical data have not established a link between filgrastim use during pregnancy and the occurrence of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1, 157, 201, 202 Published reports have described transplacental movement of filgrastim in pregnant women when given ≤30 hours prior to preterm delivery (≤30 weeks gestation).1, 157, 201, 202 In pregnant rats, no maternal or fetal effects were observed at filgrastim doses up to 58 times the human dose.1, 157, 201, 202 Adverse effects were noted in pregnant rabbits with filgrastim doses 2 to 10 times higher than the human dose.1, 157, 201, 202 No malformations were reported in the offspring of pregnant rats or rabbits given filgrastim.1, 157, 201, 202
Administration of tbo-filgrastim to pregnant rabbits during organogenesis resulted in increased spontaneous abortion and fetal malformations at systemic exposures 50-90 times the human exposure expected at the recommended human dose.145 Tbo-filgrastim should be used during pregnancy only if the potential benefit justifies the potential fetal risk.145
Case reports exist describing the use of filgrastim in breast-feeding mothers; no adverse effects were observed in exposed infants.1, 157, 201, 202 No data exist regarding the effects of filgrastim on milk production.1, 157, 201, 202 Filgrastim is excreted poorly in breastmilk and is not absorbed orally by neonates.1, 157, 201, 202 Consider the benefits of breast-feeding along with the mother's need for filgrastim against any potential adverse effects on the breast-feeding infant from filgrastim therapy or the underlying maternal condition.1, 157, 201, 202
No data are available regarding the presence of tbo-filgrastim in breastmilk, effects on the breastfed child, or effects on milk production.145
In a study of patients with cancer administered myelosuppressive chemotherapy, 15 pediatric patients (median age: 2.6 years; range, 1.2 to 9.4 years) were included and administered filgrastim doses of 5, 10, or 15 mcg/kg/day for 10 days.1, 157, 201, 202 The pharmacokinetics of filgrastim in pediatric patients after chemotherapy administration are comparable to those seen in adults administered the same weight-normalized doses.1, 157, 201, 202 Filgrastim is also well tolerated in pediatric patients receiving myelosuppressive chemotherapy, with the only consistently reported adverse event being musculoskeletal pain.1, 157, 201, 202
The effectiveness and safety of filgrastim in pediatric patients with severe chronic neutropenia have also been established in a phase 3 study.1, 157, 201, 202 In this study, 123 patients (median age: 12 years; range, 7 months to 76 years) were evaluated including 12 infants, 49 children, and 9 adolescents.1, 157, 201, 202 Additionally, a postmarketing surveillance study included 429 pediatric patients (<18 years of a range: 0.9 to 17 years) of 731 total patients with severe chronic neutropenia.1, 157, 201, 202 Results from this long-term surveillance study suggest that height and weight are not adversely affected in patients who were administered up to 5 years of filgrastim therapy.1, 157, 201, 202 Limited data from the phase 3 study did not suggest alterations in sexual maturation or endocrine function as well in patients who were followed for 1.5 years.1, 157, 201, 202
The development of cytogenetic abnormalities and transformation to MDS and AML have occurred in pediatric patients with congenital types of neutropenia administered long-term filgrastim.1, 157, 201, 202 Any relationship between filgrastim administration and the development of these adverse events is unknown.1, 157, 201, 202
The administration of filgrastim to increase survival in pediatric patients acutely exposed to myelosuppressive radiation doses is based on results from animal studies and clinical data supporting the use of filgrastim in other indications.1
Tbo-filgrastim is indicated for use in pediatric patients at least 1 month old with non-myeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia, in order to reduce the duration of severe neutropenia.145 This indication is based on evidence from studies in adults and additional safety and pharmacokinetics data from a single-arm trial of 50 pediatric patients (median age: 9.2 years; range: 1.4 to 15.9 years) with solid tumors administered tbo-filgrastim.145, 203 Overall, the pharmacokinetics and safety profile of tbo-filgrastim in the pediatric population were similar to that observed in an adult population.145, 203
In clinical studies of filgrastim-treated patients administered myelosuppressive chemotherapy involving 855 patients, 232 patients were ≥65 years of age and 22 were ≥75 years of age.1, 157, 201, 202 There were no differences in effectiveness or safety observed between these patients and younger patients.1, 157, 201, 202
In clinical studies of filgrastim-treated patients for other approved indications, there were insufficient numbers of patients ≥65 years of age to determine whether these patients responded differently than younger patients.1, 157, 201, 202
In clinical studies of tbo-filgrastim, 111 patients were ≥65 years of age and 14 patients were ≥75 years of age.145 There were no differences in effectiveness or safety observed between patients ≥65 years of age and younger patients.145
In a clinical study, increased serum concentrations of filgrastim were noted in patients with end-stage renal disease as compared to healthy subjects and patients with moderate renal impairment.1, 157, 201, 202 The pharmacokinetics of tbo-filgrastim in patients with moderate or severe renal impairment have not been studied; the presence of mild renal impairment had no effect on tbo-filgrastim pharmacokinetics.145
In a clinical study, the pharmacokinetics and pharmacodynamics of filgrastim were comparable between healthy subjects and patients with hepatic impairment (mild to moderate).1, 157, 201, 202 The pharmacokinetics of tbo-filgrastim have not been evaluated in hepatic impairment.145
The most common (≥5% difference in incidence as compared to placebo) adverse reactions in patients with nonmyeloid malignancies administered myelosuppressive chemotherapy receiving filgrastim and biosimilars include pyrexia, pain, rash, cough, and dyspnea.1, 157, 201, 202
The most common (≥2% difference in incidence as compared to placebo) adverse reactions in patients with AML receiving filgrastim and biosimilars include pain, epistaxis, and rash.1, 157, 201, 202
The most common (≥5% difference in incidence as compared to placebo) adverse reaction in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT receiving filgrastim and biosimilars includes rash.1, 157, 201, 202
The most common (≥5%) adverse reactions in patients undergoing PBPC mobilization and collection receiving filgrastim and biosimilars include bone pain, pyrexia, and headache.1, 157, 201, 202
The most common (≥5% difference in incidence as compared to placebo) adverse reactions in patients with severe chronic neutropenia receiving filgrastim and biosimilars include pain, anemia, epistaxis, diarrhea, hypoesthesia, and alopecia.1, 157, 201, 202
The most common (≥1%) adverse reaction for patients administered tbo-filgrastim is bone pain.145
No formal drug interaction studies involving the filgrastim products have been performed.1, 145, 157, 201, 202
Filgrastim, tbo-filgrastim, and biosimilars are hematopoietic agents that principally influence leukopoiesis.1, 4, 23, 32, 76, 78, 84, 85, 86, 87, 88, 89, 90, 103, 145, 157, 201, 202 The drugs appear to elicit the same pharmacologic effects produced by endogenous human granulocyte colony-stimulating factor (G-CSF).1, 4, 23, 32, 76, 157 Endogenous G-CSF, a growth factor, is a lineage-restricted CSF that principally affects the proliferation, differentiation, and activation of committed progenitor cells of the neutrophil-granulocyte lineage.1, 4, 26, 32, 42, 45, 50, 76, 84, 85, 87, 103 In addition, endogenous G-CSF enhances certain functions of mature neutrophils, including phagocytosis, chemotaxis, and antibody-dependent cellular cytotoxicity (ADCC).1, 4, 17, 32, 33, 42, 50, 87, 96, 103
Like endogenous G-CSF, filgrastim, tbo-filgrastim, and biosimilars appear to act directly on neutrophil progenitor target cells (granulocyte colony-forming units [CFU-G]) by binding to G-CSF receptors on their cell surfaces.1, 32, 42, 50, 60, 87, 93, 94, 145, 157 How this binding to receptors results in the various intracellular events necessary to affect proliferation, differentiation, and cell function has not been fully elucidated to date.32, 60
Following subcutaneous or IV administration of filgrastim in patients with cancer chemotherapy-induced neutropenia, there is an initial (within 5-60 minutes) decrease in the absolute neutrophil count (ANC) to below baseline levels.4, 9, 23, 76, 86, 87 Within 1-4 hours after administration, however, the neutrophil count begins to increase rapidly and generally exceeds baseline levels within 24 hours.4, 23, 76, 86, 87, 88, 89, 90 The initial decrease in neutrophil count may occur because of margination of neutrophils to blood vessel walls, and the subsequent increase may occur as the result of demargination and mobilization of mature neutrophils from the bone marrow and/or other tissues.4, 76, 87, 103 The increase in neutrophil count in response to filgrastim generally is dose dependent.1, 4, 23, 26, 36, 86, 87 Following discontinuance of the drug in patients with chemotherapy-induced neutropenia, a 50% decrease in the ANC generally occurs within 24 hours and the ANC returns to pretreatment levels within 1-7 days.1, 76, 87, 90
In healthy individuals, the increase in ANC is sustained throughout the period of filgrastim administration, although transient decreases generally continue to be observed with each dose.95 In patients with chemotherapy-induced neutropenia, filgrastim reduces the duration and severity of neutropenia1, 36 but generally does not eliminate the ANC nadir.26 In a study in patients with small cell lung cancer receiving myelosuppressive chemotherapy, the ANC nadir persisted for 10-15 days in patients not receiving filgrastim but for only 2-3 days in those receiving the drug.26
Filgrastim cannot increase neutrophil counts in the absence of progenitor target cells capable of responding to the drug, and the magnitude of the neutrophil response depends on the absolute numbers of target cells available.42 Patients who previously have received prolonged chemotherapy or excessive radiation generally are less responsive to filgrastim than those who have not received such treatment.4, 23, 76 Studies in patients with chemotherapy-induced neutropenia and patients with cyclic neutropenia or myelodysplastic syndromes receiving filgrastim indicate that the time to neutrophil response and the percentage of patients responding to the drug are not age dependent since geriatric patients (those 65 years of age or older) appear to respond the same as younger adults.47
Results of in vitro studies evaluating the neutrophils produced in response to filgrastim therapy indicate that these cells have a normal survival time and function normally, at least in terms of phagocytic activity and chemotaxis.1, 17, 23, 25, 30, 34, 53, 76, 87, 91, 96 Neutrophils harvested from patients with various cancers (e.g., small cell lung carcinoma, transitional cell carcinoma of the urothelium) receiving filgrastim are at least as functionally active as those harvested from healthy individuals not receiving the drug.76, 89
Filgrastim exhibits nonlinear pharmacokinetics.1, 145, 157, 201, 202 The drug is rapidly absorbed following subcutaneous injection,9, 92, 95 and peak serum concentrations of the drug generally are attained within 4-5 hours following rapid subcutaneous injection.4, 9, 92, 95 Rapid subcutaneous injection of a single 3.45- or 11.5-mcg/kg dose1, 95 of filgrastim results in peak serum concentrations averaging 4 or 49 ng/mL, respectively, within 2-8 hours;1, 9, 95 serum concentrations of the drug exceed 10 ng/mL for 8-16 hours after a single subcutaneous dose of 10 mcg/kg or more.92, 95 Most of the drug is absorbed through zero-order processes presumably through the lymphatic system.193 The absolute bioavailability of filgrastim after subcutaneous administration is 60-70%.1, 157, 193
Following subcutaneous administration of tbo-filgrastim 5 mcg/kg in patients with cancer, the median time to peak plasma concentrations of the drug was approximately 4-6 hours; no evidence of accumulation was observed with repeated dosing.145, 153 The absolute bioavailability of tbo-filgrastim following subcutaneous injection of a dose of 5 mcg/kg in healthy individuals is approximately 33%.145
Filgrastim is rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver.95 The volume of distribution of filgrastim following a single IV or subcutaneous dose reportedly averages 150 mL/kg (range: 46-384 mL/kg) in both healthy individuals and patients with cancer.1, 95 It is not known whether filgrastim is distributed into cerebrospinal fluid.95 There is published literature documenting transfer of filgrastim into human milk.1, 157 There have been reports of transplacental passage of filgrastim products in pregnant women when administered within 30 hours of preterm delivery.1, 157
Filgrastim is eliminated by both renal elimination and specific degradation by G-CSF receptors and neutrophil elastase.1, 194 Clearance is dependent on filgrastim concentration and neutrophil count; G-CSF receptor-mediated clearance is saturated by high concentrations of filgrastim and is diminished by neutropenia.1
Some data indicate that serum filgrastim concentrations decline in a biphasic manner following single IV doses.14, 86, 95 In a limited number of adults with various malignancies, the distribution half-life of filgrastim has ranged from 0.13-1.1 hours and the terminal elimination half-life has ranged from 1.8-7.2 hours.14, 86 It has been proposed that clearance is initially mediated by the binding of filgrastim to G-CSF receptors.193 When filgrastim binding sites become saturated, clearance of filgrastim decreases and elimination then occurs mostly via renal elimination.193 The manufacturer states that the elimination half-life of filgrastim following subcutaneous or IV administration averages 3.5 hours (range: 0.77-8.5 hours)1, 95, 157 in healthy individuals or patients with cancer and that the half-life of the drug following a single parenteral dose is comparable to that reported following IV doses of the drug given once daily for 2 weeks.1
The median elimination half-life of tbo-filgrastim in patients with cancer receiving chemotherapy is 3.2-3.8 hours;145, 153 in healthy individuals, median half-life of the drug was approximately 8.9 hours.153
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV or subcutaneous use | 300 mcg/mL (300 and 480 mcg) | Neupogen® (available in single-dose vials) | Amgen |
600 mcg/mL (300 and 480 mcg) | Neupogen® (available in prefilled syringes with UltraSafe® needle guard) | Amgen |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV or subcutaneous use | 600 mcg/mL (300 and 480 mcg) | Zarxio® (available in prefilled syringes with UltraSafe Passive® needle guard) | Sandoz |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV or subcutaneous use | 600 mcg/mL (300 and 480 mg) | Nivestym® (available in prefilled syringes with UltraSafe Passive® needle guard) | |
300 mcg/mL (300 and 480 mcg) | Nivestym® (available in single-dose vials) |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use | 600 mg/mL (300 mcg and 480 mcg) | Releuko® (available in prefilled syringes with UltraSafe Passive® needle guard) | Amneal Pharmaceuticals |
300 mcg/mL (300 mcg and 480 mcg) | Releuko® (available in single-dose vials) |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use | 600 mcg/mL (300 and 480 mcg) | Granix® (available in prefilled syringes with or without UltraSafe Passive® needle guard) | Teva |
300 mcg/mL (300 and 480 mg) | Granix® (available in single-dose vials) | Teva |
1. Amgen. Neupogen® (filgrastim) injection prescribing information. Thousand Oaks, CA; 2021 Feb.
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