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Filgrastim, Tbo-filgrastim

Pronunciation

Class: Hematopoietic Agents
Chemical Name: 121181-53-1
CAS Number: 121181-53-1
Brands: Neupogen, Zarxio, Granix

Introduction

In this monograph, unless otherwise stated, the term “filgrastim products” refers to filgrastim (the reference drug), filgrastim-sndz (the biosimilar), or both drugs.

Biosynthetic (recombinant DNA origin) hematopoietic agents that principally affect the proliferation and differentiation of neutrophils within the bone marrow1 3 4 12 76 78 79 80 81 82 113 145 and possibly other sites (e.g., spleen).23 42 105 113 Exert same pharmacologic effects as endogenous granulocyte colony-stimulating factor (G-CSF).1 3 4 12 76 78 79 80 81 82 113

Filgrastim-sndz is biosimilar to filgrastim (Neupogen).164 165 169 200 A biosimilar is 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.163 165 166 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between proposed biological and reference biological but does not independently establish safety and effectiveness of the proposed biological.163 166 170 Filgrastim-sndz is considered a therapeutic alternative to filgrastim; not interchangeable.168 169

Filgrastim and tbo-filgrastim are structurally and pharmacologically similar and contain a related drug substance.1 145 151 155 Tbo-filgrastim was licensed by FDA through a biologics license application (BLA), not as a biosimilar to filgrastim;155 at the time of tbo-filgrastim's submission for approval, FDA had not finalized a process for approving biosimilars.151 153 154 155

ASCO states that choice of a G-CSF (e.g., filgrastim, filgrastim-sndz, tbo-filgrastim) for the treatment of febrile neutropenia should be determined based upon convenience, cost, and the clinical situation.171

Uses for Filgrastim, Tbo-filgrastim

Cancer Chemotherapy-induced Neutropenia (Filgrastim, Filgrastim-sndz, or Tbo-filgrastim)

Management of cancer chemotherapy-induced neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive antineoplastic therapies associated with a clinically important risk of febrile neutropenia; in clinical studies, filgrastim reduced risk of infectious complications (as manifested by febrile neutropenia) and tbo-filgrastim reduced duration of severe neutropenia.1 5 6 7 8 9 10 26 32 36 65 77 102 145 152 157

Based on demonstration of biosimilarity, no clinically meaningful differences considered to exist between filgrastim-sndz and filgrastim with respect to efficacy.165 189 200

Current guidelines for the use of colony-stimulating factors (CSFs) in adults with solid tumors or nonmyeloid malignancies (e.g., lymphoma) recommend prophylaxis with CSFs based upon a patient's risk of developing febrile neutropenia following chemotherapy, taking into account the type of cancer, chemotherapy regimen, patient risk factors, and treatment intent.171 172 Prophylaxis recommended for adults with these malignancies who are at high risk of febrile neutropenia (> 20%) and can be considered for patients at intermediate risk (10–20%) if risk is due to patient risk factors and not the chemotherapy regimen.172 173 Prophylaxis is generally not recommended in patients with a low risk of febrile neutropenia (<10%). 172

Secondary prophylaxis with CSFs recommended in patients who had a neutropenic complication from a previous chemotherapy cycle (for which primary prophylaxis not received) and in whom a reduced chemotherapy dose or treatment delay would compromise disease-free or overall survival or treatment outcomes.171 172

Efficacy not established in patients receiving antineoplastic therapy associated with delayed myelosuppression (e.g., nitrosourea derivatives) or in those receiving mitomycin or myelosuppressive doses of antimetabolites (e.g., cytarabine, fluorouracil).110 113 179

Filgrastim has been used in conjunction with empiric anti-infective therapy for the treatment of chemotherapy-induced febrile neutropenia.129

Guidelines recommend that patients who develop febrile neutropenia despite receiving prophylactic treatment with CSFs should continue receiving treatment with the same CSF.172 CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.171 CSF therapy may be considered for patients who did not receive prophylaxis and develop febrile neutropenia if risk factors for infection-related complications or poor outcomes are present (e.g., patients >65 years of age, sepsis syndrome, ANC <100/mm3, anticipated or prolonged neutropenia [>10 days], pneumonia, invasive fungal infections or other clinically documented infections, hospitalization, prior episodes of febrile neutropenia).171 172

Leukemia (Filgrastim or Filgrastim-sndz)

Reduction of the time to neutrophil recovery and the duration of fever following induction or consolidation cancer chemotherapy in adults with acute myeloid leukemia (AML);1 136 137 138 157 filgrastim designated an orphan drug by FDA for the reduction in duration of neutropenia, fever, antibiotic use, and hospitalization following induction and consolidation treatment for AML.135

Use of filgrastim in patients with acute leukemia has been controversial, since results of in vitro studies indicate that certain leukemic cell lines have receptors for G-CSF and that the survival, proliferation, and differentiation of the cells are supported by CSFs.4 11 19 23 42 50 63 77 Some experts state that use of filgrastim in the treatment of myeloid leukemia should be considered investigational and undertaken with caution.11 42 77 110 113

Some guidelines state use of CSFs may be considered in patients with AML during induction therapy for patients who are septic and have a life-threatening infection in an attempt to shorten the duration of neutropenia.195 Data lacking on whether growth factors have a positive or negative impact on long-term outcome if used during consolidation therapy.195 Growth factors not routinely recommended in post-remission therapy, except in life-threatening infections or when manifestations of sepsis are present and leukemia is in remission.195

Autologous and Allogeneic Bone Marrow Transplantation (BMT) (Filgrastim or Filgrastim-sndz)

Reduction of the duration of neutropenia and neutropenia-related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative cancer chemotherapy followed by BMT;1 4 12 16 24 32 33 102 125 126 filgrastim designated an orphan drug by FDA for the treatment of neutropenia associated with BMT.135

Peripheral Blood Progenitor Cell (PBPC) Transplantation (Filgrastim or Filgrastim-sndz)

Mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis;1 72 77 filgrastim designated an orphan drug by FDA for mobilization of PBPC for collection in patients who will receive myeloablative or myelosuppressive cancer chemotherapy.135

Also used for acceleration of myeloid engraftment following autologous PBPC transplantation.1 72 77

Congenital, Cyclic, and Idiopathic Neutropenias (Filgrastim or Filgrastim-sndz)

Reduction of the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia,1 4 13 20 32 46 73 104 157 cyclic neutropenia,1 12 15 104 157 or acquired idiopathic neutropenia;1 4 12 30 62 157 filgrastim designated an orphan drug by FDA for treatment of severe chronic neutropenia (ANC <500/m3).135

Initiate therapy in patients with severe chronic neutropenia only after a diagnosis of congenital, cyclic, or idiopathic neutropenia has been confirmed and other diseases associated with neutropenia have been excluded.1 157

Hematopoietic Syndrome of Acute Radiation Syndrome (Filgrastim)

Increase survival in patients acutely exposed to myelosuppressive doses of radiation;1 158 196 designated an orphan drug by FDA for treatment of patients at risk of developing myelosuppression after a radiologic or nuclear incident.135

Myelodysplastic Syndromes and Aplastic Anemia (Filgrastim)

Has been used to increase leukocyte counts in adults with myelodysplastic syndrome (MDS)12 28 29 32 35 37 55 57 61 75 77 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, it is unclear whether filgrastim will alter (either increase or decrease) the rate of progression to acute myeloid leukemia or alter the usually fatal outcome of the disease.4 35 37 77 Designated an orphan drug by FDA for treatment of MDS.135 Safety and efficacy for this use not established;1 use generally should be limited to experts in such therapy.110 113

Has been used with some success to increase leukocyte counts in a limited number of children 1–17 years of age with moderate to severe aplastic anemia.4 12 18 40 Use generally should be limited to experts in such therapy.110 113

Neutropenia Associated with HIV Infection and Antiretroviral Therapy (Filgrastim)

Treatment to correct or minimize HIV-associated neutropenia and/or drug-induced neutropenia.4 25 26 27 31 38 52 54 59 77 130 131 132

Treatment, alone or in conjunction with epoetin alfa, to ameliorate the hematologic toxicity (severe anemia and/or granulocytopenia) associated with zidovudine therapy in adults with AIDS or AIDS-related complex (ARC).4 25 59 77

Filgrastim designated an orphan drug by FDA for the treatment of HIV-infected patients who, in addition, are afflicted with cytomegalovirus retinitis and are being treated with ganciclovir.135

Filgrastim, Tbo-filgrastim Dosage and Administration

Administration

Filgrastim or Filgrastim-sndz

Depending on use, administer filgrastim or filgrastim-sndz by IV infusion1 4 6 8 10 11 12 13 14 15 18 19 20 24 29 36 65 87 91 92 110 157 or by sub-Q injection.1 2 4 7 9 10 11 12 13 15 17 20 28 35 37 48 58 61 76 92 102 110 157 Filgrastim also has been administered by continuous sub-Q infusion.9 11 12 16 72 110 Sub-Q injection is most convenient for self-administration4 7 11 13 15 17 35 48 76 102 and especially useful for prolonged maintenance therapy.4 6 13 15 17 28 48 102

Patient may self-administer filgrastim or filgrastim-sndz.1 2 149 157 162 (See Advice to Patients.)

Filgrastim-sndz prefilled syringes may not accurately measure volumes <0.3 mL; direct administration of a volume of filgrastim-sndz <0.3 mL not recommended.157

Do not administer filgrastim or filgrastim-sndz within 24 hours before or after myelosuppressive cancer chemotherapy because many antineoplastic agents target rapidly proliferating cells.1 157

When used in patients undergoing myeloablative chemotherapy followed by BMT, administer first dose of filgrastim or filgrastim-sndz ≥24 hours after cytotoxic therapy and ≥24 hours after BMT.1 125 126 157

Do not shake.1 157

Vials and prefilled syringes are for single use only.1 157 Discard any unused portion.1 157

For solution and drug compatibility information, see Compatibility under Stability.

Tbo-Filgrastim

Administer tbo-filgrastim sub-Q.145

Patient may self-administer tbo-filgrastim. 145 (See Advice to Patients.)

Do not shake.145 Prefilled syringes are for single use only; discard any unused portion.145

First dose of tbo-filgrastim should be administered ≥24 hours after myelosuppressive chemotherapy; do not administer drug within 24 hours before such chemotherapy.145 Do not administer first dose of tbo-filgrastim within 24 hours before myelosuppressive chemotherapy.145

For solution and drug compatibility information, see Compatibility under Stability.

IV Administration (Filgrastim or Filgrastim-sndz)

Dilution

If required, may dilute with 5% dextrose injection.1 157 If diluted to a concentration of 5–15 mcg/mL, add albumin human to the infusion solution to a final concentration of 2 mg/mL (0.2%) to minimize adsorption of the drug to drug delivery system components.1 69 110 157 Do not dilute to a final concentration of <5 mcg/mL.1 157 199

Do not dilute with 0.9% sodium chloride injection since precipitation may occur.1 156 157

Rate of Administration

If administered by IV infusion in patients with cancer chemotherapy-induced neutropenia, may administer as a brief IV infusion (e.g., over 15–30 minutes)1 8 15 18 19 24 29 36 65 76 87 110 113 157 or by continuous IV infusion.1 5 6 157

If administered by IV infusion in patients undergoing BMT, manufacturers recommend an infusion duration of no longer than 24 hours.1 126 157

Sub-Q Administration (Filgrastim, Filgrastim-sndz, or tbo-Filgrastim)

Recommended sites for sub-Q injection include upper back portion of upper arms, abdomen (except for 2-inch area around navel), front of middle thighs, or upper outer areas of the buttocks.1 2 145 149 157 162

Rotate injection sites daily; avoid any area that is tender, red, bruised, scaly, hard, or has stretch marks or scars.2 145 149 162

Dosage

Pediatric Patients

Cancer Chemotherapy-induced Neutropenia (Filgrastim or Filgrastim-sndz)
IV or Sub-Q

Individualize dosage depending on type and dosage of myelosuppressive cancer chemotherapy.1 4 48 77 157 Initially, 5 mcg/kg once daily.1 4 5 6 8 19 36 77 157 If response inadequate after 5–7 days, may increase dosage in increments of 5 mcg/kg with each chemotherapy cycle according to the duration and severity of the ANC nadir.1 4 110 157

Continue treatment for up to 2 weeks or until ANC reaches 10,000/mm3 following the expected chemotherapy-induced ANC nadir.1 4 113 110 157

Discontinue if ANC increases to >10,000/mm3 following expected chemotherapy-induced neutrophil nadir; such ANC levels may not result in additional clinical benefit and may increase potential for complications from excessive leukocytosis.1 157

Congenital, Cyclic, and Idiopathic Neutropenias (Filgrastim or Filgrastim-sndz)
Congenital Neutropenia
Sub-Q

Initially, 6 mcg/kg twice daily; individualize dosage according to clinical course and neutrophil count.1 13 20 133 157

Cyclic or Idiopathic Neutropenia
Sub-Q

Initially, 5 mcg/kg once daily; individualize dosage according to clinical course and neutrophil count.1 4 15 133 157

Hematopoietic Syndrome of Acute Radiation Syndrome (Filgrastim)
Sub-Q

10 mcg/kg once daily (based on studies in animals and clinical use data from other indications); administer as soon as possible after suspected or confirmed exposure to radiation doses >2 Gy.1

Continue treatment until ANC remains >1000/mm3 for 3 consecutive CBCs or >10,000/mm3 after radiation-induced nadir.1

Neutropenia Associated with HIV Infection and Antiretroviral Therapy (Filgrastim)
Sub-Q

Adolescents: 5–10 mcg/kg once daily for 2–4 weeks.131

Adults

Cancer Chemotherapy-induced Neutropenia (Filgrastim or Filgrastim-sndz)
IV or Sub-Q

Individualize dosage depending on type and dosage of myelosuppressive cancer chemotherapy.1 4 48 77 157 Initially, 5 mcg/kg once daily.1 4 5 6 8 19 36 77 157 Administer ≥24 hours after cytotoxic chemotherapy; do not administer within the 24-hour period prior to such chemotherapy.1 157 If response inadequate after 5–7 days, may increase dosage in increments of 5 mcg/kg with each chemotherapy cycle, according to the duration and severity of the ANC nadir.1 4 110 157

Transient increase in neutrophil count typically seen 1–2 days after initiation of therapy.1 157 To ensure sustained response, continue treatment for up to 2 weeks until ANC reaches 10,000/mm3 following the expected chemotherapy-induced ANC nadir.1 4 113 110 157

Discontinue if ANC increases to >10,000/mm3 following expected chemotherapy-induced neutrophil nadir;1 95 113 such ANC levels may not result in additional clinical benefit and may increase potential complications from excessive leukocytosis (e.g., bone pain).1 36 95 157

Cancer Chemotherapy-induced Neutropenia (Tbo-filgrastim)
Sub-Q

5 mcg/kg once daily.145 Administer first dose ≥24 hours after myelosuppressive cancer chemotherapy.145 Continue treatment until expected chemotherapy-induced neutrophil nadir has passed and ANC has recovered to within normal range.145

Bone Marrow Transplantation (Filgrastim or Filgrastim-sndz)
IV

Initially, 10 mcg/kg once daily.1 157 Administer first dose ≥24 hours after cytotoxic cancer chemotherapy and ≥24 hours after BMT.1 125 126 157 Reduce dosage to 5 mcg/kg once daily when ANC is >1000/mm3 for 3 consecutive days.1 127 157 Discontinue filgrastim or filgrastim-sndz if ANC remains >1000/mm3 for an additional 3 consecutive days.1 157 If ANC is <1000/mm3 following discontinuance of filgrastim or filgrastim-sndz, reinitiate therapy at 5 mcg/kg once daily.1 157 If ANC is <1000/mm3 at any time when the 5-mcg/kg daily dosage is being used, increase dosage to 10 mcg/kg once daily and repeat preceding steps.1 157

PBPC Transplantation (Filgrastim or Filgrastim-sndz)
Mobilization of Hematopoietic Progenitor Cells
Sub-Q

10 mcg/kg once daily.1 157 Manufacturers recommend that filgrastim or filgrastim-sndz be administered at least 4 days prior to first leukapheresis and continued until the last leukapheresis is performed.1 157 Optimum duration of therapy not established; in clinical trials, filgrastim was administered for 6–7 days with leukapheresis on days 5, 6, and 7.1 157

Monitor neutrophil counts after 4 days; discontinue filgrastim or filgrastim-sndz if WBC count increases to >100,000/mm3.1 157

Administration following reinfusion of PBPC collection: In clinical trials, 5–24 mcg/kg of filgrastim once daily given until a sustainable ANC (≥500/mm3) attained.1 157

Congenital, Cyclic, and Idiopathic Neutropenias (Filgrastim or Filgrastim-sndz)
Congenital Neutropenia
Sub-Q

Initially, 6 mcg/kg twice daily; individualize dosage according to clinical course and neutrophil count.1 13 20 133 157

Cyclic or Idiopathic Neutropenia
Sub-Q

Initially, 5 mcg/kg once daily; individualize dosage according to clinical course and neutrophil count.1 4 15 133 157

Hematopoietic Syndrome of Acute Radiation Syndrome (Filgrastim)
Sub-Q

10 mcg/kg once daily; administer as soon as possible after suspected or confirmed exposure to radiation doses >2 Gy.1 196

Continue treatment until ANC remains >1000/mm3 for 3 consecutive CBCs or >10,000/mm3 after radiation-induced nadir.1

Myelodysplastic Syndromes and Aplastic Anemia (Filgrastim)
Myelodysplastic Syndromes
IV

Dosages of 50–400 mcg/m2 administered once daily over 30 minutes have been used.28 29 35 37 61

Sub-Q

Dosages of 0.3–10 mcg/kg administered once daily have been used.28 29 35 37 61

Neutropenia Associated with HIV Infection and Antiretroviral Therapy (Filgrastim)
Sub-Q

5–10 mcg/kg once daily for 2–4 weeks.131

Cautions for Filgrastim, Tbo-filgrastim

Contraindications

  • Filgrastim or filgrastim-sndz: Known history of serious allergic reactions to human G-CSFs (e.g., filgrastim or pegfilgrastim products).1 157

  • Tbo-filgrastim: Manufacturer states none known.145

Warnings/Precautions

Warnings

Splenic Rupture

Splenic rupture (including fatalities) reported following administration of filgrastim products.1 144 157 Although no cases in clinical trials with tbo-filgrastim, consider possible risk.153

Evaluate patients experiencing left upper abdominal and/or shoulder tip pain for splenomegaly or splenic rupture.1 145 157 Manufacturer of tbo-filgrastim states to discontinue drug if such symptoms occur.145

Respiratory Effects

Acute respiratory distress syndrome (ARDS) reported in patients receiving filgrastim products.1 145 157 Although no cases to date with tbo-filgrastim, consider possible risk.153

If fever, lung infiltrates, or respiratory distress develops, evaluate patient for the presence of ARDS.1 157 If ARDS occurs, discontinue filgrastim, filgrastim-sndz, or tbo-filgrastim therapy.1 145 157

Sickle Cell Disease

Severe, sometimes fatal, sickle cell crisis reported in patients with sickle cell trait or sickle cell disease receiving filgrastim products.1 157 Although no cases to date with tbo-filgrastim, consider possible risk.145 153

Prior to administering filgrastim, filgrastim-sndz, or tbo-filgrastim in patients with sickle cell disease, consider potential risks versus benefits of therapy.1 145 157 Discontinue tbo-filgrastim if sickle cell crisis occurs.145

Severe Chronic Neutropenia

Initiate filgrastim or filgrastim-sndz therapy in patients with severe chronic neutropenia only after a diagnosis of congenital, cyclic, or idiopathic neutropenia has been confirmed and other diseases associated with neutropenia have been excluded; safety and efficacy in the treatment of neutropenia caused by other hematopoietic disorders (e.g., MDS) not established.1 157

Cytogenetic abnormalities, MDS, and AML reported during therapy with filgrastim products in patients with severe chronic neutropenia.1 157 The risk of developing MDS or AML appears to be limited to patients with congenital neutropenia.1 The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued use of the drug in patients with abnormal cytogenetics or MDS are unknown.1 157

Carefully consider risks and benefits of continuing filgrastim therapy if abnormal cytogenetics or myelodysplasia develops in patients with severe chronic neutropenia.1 157

Sensitivity Reactions

Hypersensitivity Reactions

Risk of serious allergic reactions, including anaphylaxis, with filgrastim, filgrastim-sndz, or tbo-filgrastim.1 145 154 157 Do not use in patients with known hypersensitivity to filgrastim or related drugs (e.g., pegfilgrastim).1 145 157 (See Contraindications under Cautions.)

If a serious allergic reaction occurs, permanently discontinue the drug.1 145 157 May administer antihistamines, corticosteroids, bronchodilators, and/or epinephrine to reduce allergic-type symptoms.145 154

Latex Sensitivity

Some packaging components (i.e., needle cover) of prefilled syringes of filgrastim or filgrastim-sndz contain natural latex proteins in the form of dry natural rubber.1 157 Some individuals may be hypersensitive to natural latex proteins; rarely, hypersensitivity reactions to natural latex proteins have been fatal.146 147 148

General Precautions

Cancer Chemotherapy and Radiation Therapy

Filgrastim therapy may allow use of higher cumulative cancer chemotherapy dosages; possible increased risk of thrombocytopenia, anemia, and nonhematologic adverse effects associated with the chemotherapy regimen.1 6 8 43 64 102

Safety and efficacy of concomitant radiation therapy or cytotoxic chemotherapy not established.1 157 Do not administer filgrastim or filgrastim-sndz concomitantly with radiation therapy.1 157 Do not administer filgrastim, filgrastim-sndz, or tbo-filgrastim during the 24 hours before or after administration of cytotoxic chemotherapy.1 145 157 (See Interactions.)

Effect on Malignant Cells

The possibility that filgrastim, filgrastim-sndz, or tbo-filgrastim could act as a growth factor for any tumor type, particularly myeloid malignancies, has not been excluded.1 3 11 42 49 64 76 77 145 157 Safety of filgrastim products in patients with chronic myeloid leukemia (CML) or MDS not established.1 157 Tbo-filgrastim not FDA-labeled for use in patients with myeloid malignancies or myelodysplasia.145

When filgrastim or filgrastim-sndz is used for mobilization of hematopoietic progenitor cells, possible release of tumor cells from the marrow and subsequent collection in the leukapheresis product;1 157 effect of reinfusion of tumor cells not well studied and limited data available to date are inconclusive.1 157

Excessive Leukocytosis

Marked leukocytosis (WBC counts ≥100,000/mm3) reported occasionally with filgrastim or tbo-filgrastim therapy.1 23 145 Manufacturers of filgrastim and filgrastim-sndz recommend that WBC counts be monitored to avoid potential complications of excessive leukocytosis.1 95 157 (See Laboratory Monitoring under Cautions.)

Immunogenicity

Potential risk of immunogenicity.1 145 154 157 Available data suggest that a small proportion of patients receiving filgrastim develop binding antibodies; however, nature and specificity of these antibodies not adequately studied.1 Cytopenias resulting from an antibody response to exogenous growth factors reported rarely in patients treated with other recombinant growth factors.1

Binding or neutralizing antibodies to tbo-filgrastim not detected in principal efficacy study; however, further study needed to determine immunogenicity potential of the drug.152

Dermatologic Effects

Cutaneous vasculitis reported with filgrastim products,1 4 11 12 20 62 157 principally in patients with severe chronic neutropenia receiving long-term therapy.1 Withhold filgrastim or filgrastim-sndz therapy in patients with cutaneous vasculitis; may be restarted at a reduced dose when symptoms resolve and the ANC has decreased.1 157

Laboratory Monitoring

Perform CBC and platelet counts prior to initiation of cancer chemotherapy and routinely (twice weekly) during filgrastim, filgrastim-sndz, or tbo-filgrastim therapy for chemotherapy-induced neutropenia.1 102 113 145 157

Perform CBC and platelet counts frequently in patients receiving filgrastim or filgrastim-sndz following BMT.1 157

Monitor neutrophil counts after 4 days of filgrastim or filgrastim-sndz therapy for mobilization of PBPC.1 157

In patients with severe chronic neutropenia, perform CBC with differential and platelet counts prior to filgrastim therapy, during the initial 4 weeks of therapy, and during the first 2 weeks following any dosage adjustment; once patient is clinically stable, may perform hematologic monitoring once monthly during the first year of treatment.1 157 Thereafter, monitor less frequently if patient is clinically stable.1 157

Specific Populations

Pregnancy

Category C.1 145 157

No adequate and well-controlled studies of filgrastim, filgrastim-sndz, or tbo-filgrastim in pregnant women.1 145 157 Animal studies (e.g., rat, rabbit) suggest a possibility of adverse embryofetal effects.1 145 157

Use only if potential benefits justify potential risk to fetus.1 95 145 157

Lactation

Not known whether filgrastim, filgrastim-sndz, or tbo-filgrastim is distributed into milk; caution advised.1 95 145 157

Pediatric Use

Pharmacokinetics of filgrastim in pediatric patients after cancer chemotherapy similar to that of adults receiving same weight-normalized doses; no age-related differences in pharmacokinetics of filgrastim products.1 157

Cytogenetic abnormalities and transformation to MDS and AML have occurred during filgrastim therapy in pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, Schwachman-Diamond syndrome).1 The relationship between these events and filgrastim is unknown.1

Adverse effects reported in children with cancer receiving filgrastim are similar to those reported in adults.1 Alterations in growth and development, sexual maturation, or endocrine function not reported.1 Possible subclinical splenomegaly or hepatosplenomegaly.1 Decreased bone density and osteoporosis reported in pediatric patients receiving long-term treatment with filgrastim products.1 157

Filgrastim-sndz prefilled syringes may not accurately measure volumes <0.3 mL; direct administration of a volume of filgrastim-sndz <0.3 mL not recommended.157

Safety and efficacy of tbo-filgrastim not established in pediatric patients <18 years of age.145

Geriatric Use

Safety and efficacy profiles similar to those in younger adults receiving filgrastim, filgrastim-sndz, or tbo-filgrastim following myelosuppressive cancer chemotherapy.1 145 157 Clinical studies for other filgrastim indications (e.g., BMT, PBPC mobilization, severe chronic neutropenia) did not include sufficient number of individuals ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Filgrastim or filgrastim-sndz: No dosage adjustment required.1 157

Tbo-filgrastim: Pharmacokinetic profile not evaluated in patients with hepatic impairment.145

Renal Impairment

Filgrastim or filgrastim-sndz: No dosage adjustment required.1 157

Tbo-filgrastim: No effect of mild renal impairment (Clcr 60–89 mL/minute) on pharmacokinetics of tbo-filgrastim; not evaluated in patients with moderate or severe renal impairment.145

Common Adverse Effects

Cancer chemotherapy-induced neutropenia (filgrastim or filgrastim-sndz): Pyrexia,1 157 nausea,1 157 thrombocytopenia,1 157 fatigue,1 157 back pain,1 157 dizziness,1 157 cough,1 157 rash,1 157 chest pain,1 157 dyspnea,1 157 pain,1 157 bone pain,1 157 172 179 arthralgia,1 157 increase in serum LDH,1 157 increase in alkaline phosphatase,1 157 179 anemia,1 157 constipation,1 157 diarrhea,1 157 oral pain,1 157 vomiting,1 157 asthenia,1 157 malaise,1 157 peripheral edema,1 157 decreased hemoglobin,1 157 decreased appetite,1 157 oropharyngeal pain,1 157 alopecia.1 157

Tbo-filgrastim: Bone pain.145 153 154

AML (filgrastim or filgrastim-sndz): Epistaxis,1 157 back pain,1 157 pain in extremity,1 157 erythema,1 157 maculopapular rash.1 157

Autologous and allogeneic BMT (filgrastim or filgrastim-sndz): Rash and hypersensitivity,1 157 thrombocytopenia,1 157 anemia,1 157 hypertension,1 157 sepsis,1 157 bronchitis,1 157 insomnia.1 157

PBPC transplantation (filgrastim or filgrastim-sndz): Bone pain,1 157 pyrexia,1 157 increased alkaline phosphatase,1 157 headache.1 157

Congenital, cyclic, and idiopathic neutropenias (filgrastim or filgrastim-sndz): Arthralgia, bone pain, back pain, muscle spasm, musculoskeletal pain,1 157 pain in extremity,1 157 splenomegaly,1 157 anemia,1 157 upper respiratory infection,1 157 urinary tract infection,1 157 epistaxis,1 157 chest pain,1 157 diarrhea,1 157 hypoesthesia,1 157 alopecia.1 157

Interactions for Filgrastim, Tbo-filgrastim

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antineoplastic agents

Sensitivity of rapidly dividing cells to cytotoxic cancer chemotherapy may be increased1 157

Safety and efficacy of concomitant administration not established;1 157 do not administer filgrastim, filgrastim-sndz, or tbo-filgrastim within 24 hours of administration of an antineoplastic agent1 145 157

Bone imaging

Increased hematopoietic activity of the bone marrow may cause transient positive bone-imaging changes1 145 157

Consider possibility of such interference when interpreting results of bone-imaging tests1 145 157

Lithium

Possible increased myeloproliferative effects with concomitant tbo-filgrastim therapy145

Use with caution145

Filgrastim, Tbo-filgrastim Pharmacokinetics

Absorption

Bioavailability

Filgrastim or filgrastim-sndz: Rapidly absorbed following sub-Q injection,9 11 12 92 95 192 with peak serum concentrations generally attained within 4–5 hours.4 9 11 12 92 95 Absolute bioavailability following sub-Q injection is approximately 60–70%.1 157 193

Tbo-filgrastim: Median time to peak plasma concentrations approximately 4–6 hours following sub-Q dose.145 Absolute bioavailability following sub-Q injection is approximately 33%.145

Special Populations

Pharmacokinetics of filgrastim not available in patients acutely exposed to myelosuppressive doses of radiation.1 AUC in irradiated nonhuman primates at 10-mcg/kg dose of filgrastim similar to that in humans at 5 mcg/kg.1 Exposure to filgrastim at dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation expected to exceed exposures of filgrastim at dose of 10 mcg/kg in irradiated nonhuman primates.1

Distribution

Extent

Filgrastim is rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver.95

Not known whether filgrastim distributes into cerebrospinal fluid.192

Transplacental passage of filgrastim products reported when administered ≤30 hours prior to preterm delivery.1 157

Not known whether filgrastim, filgrastim-sndz, or tbo-filgrastim distributes into human milk.1 145 157

Elimination

Elimination Route

Filgrastim eliminated renally and via specific degradation by G-CSF receptors and neutrophil elastase.1 194 Clearance dependent on filgrastim concentration and neutrophil count; G-CSF receptor-mediated clearance saturated by high concentrations of filgrastim and diminished by neutropenia.1

Half-life

Filgrastim or filgrastim-sndz: About 3.5 hours.1 157 192

Tbo-filgrastim: About 3.2–3.8 hours (median) in patients with cancer receiving chemotherapy; approximately 8.9 hours in healthy individuals.145 153

Stability

Storage

Parenteral

Filgrastim or filgrastim-sndz: 2–8°C.1 157 Do not freeze; protect from light.1 157 May be allowed to reach room temperature for up to 24 hours before use.1 157

Tbo-filgrastim: 2–8°C; protect from light.145 May be removed from refrigerator storage for a single period of up to 5 days and kept at 23–27°C; if not used, may return to refrigerator until expiration date.145 Stable when exposed to temperatures of -1 to -5°C for up to 72 hours and -15 to -25°C for up to 24 hours.145

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility (Filgrastim or Filgrastim-sndz)

Incompatible

Sodium chloride 0.9%1 2 69 110 157

Compatible

Dextrose 5%1 157

Drug Compatibility (Filgrastim)
Y-Site Compatibility156

Compatible

Acyclovir sodium

Allopurinol sodium

Amikacin sulfate

Aminophylline

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefazolin sodium

Cefotetan disodium

Ceftazidime

Chlorpromazine HCl

Cisplatin

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Daunorubicin HCl

Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Famotidine

Floxuridine

Fluconazole

Fludarabine phosphate

Gallium nitrate

Ganciclovir sodium

Granisetron HCl

Haloperidol lactate

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Leucovorin calcium

Lorazepam

Mechlorethamine HCl

Melphalan HCl

Meperidine HCl

Mesna

Methotrexate sodium

Metoclopramide HCl

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Potassium chloride

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Streptozocin

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Amphotericin B

Cefotaxime sodium

Cefoxitin sodium

Ceftaroline fosamil

Ceftriaxone sodium

Cefuroxime sodium

Clindamycin phosphate

Dactinomycin

Etoposide

Fluorouracil

Furosemide

Heparin sodium

Mannitol

Methylprednisolone sodium succinate

Metronidazole

Mitomycin

Prochlorperazine edisylate

Thiotepa

Variable

Gentamicin sulfate

Imipenem–cilastatin sodium

Actions

  • Influences leukopoiesis;1 4 12 23 32 76 78 84 85 86 87 88 89 90 103 145 157 affects the proliferation and differentiation of neutrophils within the bone marrow1 3 4 12 76 78 79 80 81 82 113 145 157 and possibly other sites (e.g., spleen).23 42 105 113

  • Binds directly to G-CSF receptors on neutrophil progenitor target cell surfaces.1 32 42 50 60 87 93 94 145 157 Stimulates neutrophil proliferation, thereby increasing neutrophil counts and activity.10 12 76 86 145

  • Increases and sustains the ANC throughout administration; however, an initial transient decline in ANC has been observed with each dose of filgrastim.4 9 11 12 23 76 86 87 192

  • Filgrastim also may increase lymphocyte and monocyte counts;1 4 11 12 26 32 76 87 89 however, does not affect eosinophil or basophil counts4 11 12 87 89 nor consistently affect hemoglobin levels or hematocrit;4 11 12 transient dose-dependent decrease in platelet count may occur.4 10 11 35 59 61 87

  • Filgrastim or filgrastim-sndz reduces duration and severity of neutropenia in patients with cancer chemotherapy-induced neutropenia;1 11 36 157 ANC nadir occurs sooner and there is accelerated recovery of neutrophil counts.1 Tbo-filgrastim has been shown to reduce duration of severe neutropenia in patients with chemotherapy-induced neutropenia.145

Advice to Patients

  • Importance of instructing patients to read the manufacturer's product information and instructions for use.1 145 157

  • Risk of hypersensitivity reactions, including the possibility of anaphylaxis.1 145 157 Importance of immediately informing clinician if symptoms of serious allergic reactions (e.g., rash, facial edema, urticaria, wheezing, dyspnea, hypotension, tachycardia) occur.1 145 157

  • Importance of advising patients about the possibility of bone pain, which can usually be relieved by the use of analgesics such as acetaminophen or NSAIAs.2 145 162

  • Risk of splenomegaly or splenic rupture; importance of immediately informing clinician if abdominal pain, left upper quadrant pain, or left shoulder pain occurs.1 2 145 157

  • Risk of ARDS; importance of immediately informing clinician if shortness of breath, difficulty breathing, or rapid breathing occurs.1 2 145 157 162

  • Risk of glomerulonephritis (filgrastim or filgrastim-sndz); importance of immediately informing clinician if facial or ankle swelling, decreased urine production, blood in urine, or dark colored urine occurs.1 157

    Risk of cutaneous vasculitis (filgrastim or filgrastim-sndz); importance of informing clinician if signs and symptoms of vasculitis (e.g., erythema, purpura) occur.1 157

  • Importance of discussing potential risks (e.g., sickle cell crisis, death) and benefits of therapy for patients with sickle cell disease.1 2 145 157 162

  • Importance of immediately informing clinician if signs and symptoms of infection (e.g., fever, redness, swelling) occur while receiving tbo-filgrastim.145

  • If filgrastim, filgrastim-sndz, or tbo-filgrastim is to be self-administered, importance of providing the patient with instruction on proper dosage and administration of the drug, including aseptic technique and safe disposal of needles, syringes, and unused drug.1 2 145 149 157 162

  • Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.1 2 145 149 157 162 Importance of advising women not to become pregnant while receiving tbo-filgrastim; advise of potential for fetal harm if pregnancy occurs.145

    Encourage women who become pregnant during filgrastim therapy to enroll in the manufacturer's pregnancy surveillance program at 1-800-77-AMGEN (1-800-772-6436).110

  • Importance of informing patients acutely exposed to myelosuppressive doses of radiation that filgrastim is FDA-labeled for the treatment of hematopoietic syndrome of acute radiation syndrome based on efficacy studies conducted in animals (not conducted in humans for ethical reasons).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., sickle cell disease).1 2 145 157

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

Filgrastim (Recombinant DNA Origin)

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

Filgrastim-sndz (Recombinant DNA Origin)

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

Tbo-filgrastim (Recombinant DNA Origin)

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

AHFS DI Essentials. © Copyright 2017, Selected Revisions November 11, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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2. Amgen. Neupogen (filgrastim) injection patient information. Thousand Oaks, CA; 2015 Jul.

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103. Lang CH, Bagby GJ, Dobrescu C et al. Effect of granulocyte colony-stimulating factor on sepsis-induced changes in neutrophil accumulation and organ glucose uptake. J Infect Dis. 1992; 166:336-43. [PubMed 1378872]

104. Migliaccio AR, Migliaccio G, Dale DC et al. Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo. Blood. 1990; 75:1951-9. [PubMed 1692489]

105. Dale DC, Hammond WP, Gabrilove J et al. Long term treatment of severe chronic neutropenia with recombinant human granulocyte factor (r-metHuG-CSF). Blood. 1990; 76(Suppl 1):139.

106. Fazio MT, Glaspy JA. The impact of granulocyte colony-stimulating factor on quality of life in patients with severe chronic neutropenia. Oncol Nurs Forum. 1991; 18:1411-4. [PubMed 1722310]

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