Generic Name: filgrastim

Brand Names: Neupogen

Uses

Chemotherapy-induced Neutropenia

Reduction of the risk of infectious complications (as manifested by febrile neutropenia) in patients with nonmyeloid malignancies receiving myelosuppressive antineoplastic therapy that is associated with a clinically important risk of severe neutropenia with fever.

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).

Has been used in conjunction with empiric anti-infective therapy for the treatment of chemotherapy-induced febrile neutropenia†.

Autologous and Allogeneic Bone Marrow Transplantation

Reduction of the duration of neutropenia and neutropenia-related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT); designated an orphan drug by FDA for the treatment of neutropenia associated with BMT.

Peripheral Blood Progenitor Cell Transplantation

Mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis; designated an orphan drug by FDA for mobilization of peripheral blood progenitor cells (PBPC) for collection in patients who will receive myeloablative or myelosuppressive chemotherapy.

Acceleration of myeloid engraftment following autologous PBPC transplantation.

Congenital, Cyclic, and Idiopathic Neutropenias

Reduction of the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or acquired idiopathic neutropenia; designated an orphan drug by FDA for treatment of severe chronic neutropenia (ANC <500/m³). 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.

Myelodysplastic Syndromes and Aplastic Anemia

Has been used to increase leukocyte counts in adults with myelodysplastic syndrome† (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); 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. Safety and efficacy for this use not established; use generally should be limited to experts in such therapy.

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†. Use generally should be limited to experts in such therapy.

Leukemias

Reduction of the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in adults with acute myeloid leukemia (AML).

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. Some experts state that use of filgrastim in the treatment of myeloid leukemias should be considered investigational and undertaken with caution.

Neutropenia Associated with HIV Infection and Antiretroviral Therapy

Treatment to correct or minimize HIV-associated neutropenia and/or drug-induced neutropenia†.

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).

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.

Dosage and Administration

Administration

Administer by IV infusion or by sub-Q injection or infusion. Sub-Q injection is most convenient for self-administration and especially useful for prolonged maintenance therapy.

Do not administer filgrastim within 24 hours before or after therapy with antineoplastic drugs.

When filgrastim is used in patients undergoing myeloablative chemotherapy followed by BMT, administer the first dose of filgrastim ≥24 hours after cytotoxic therapy and ≥24 hours after BMT.

Do not shake the injection, since frothing or bubble formation may occur.

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

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

IV Administration

Dilution

Can be diluted with 5% dextrose injection. When filgrastim is 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. Do not dilute to a final concentration of <5 mcg/mL.

Rate of Administration

Patients with chemotherapy-induced neutropenia: Administer by IV infusion over 15–30 minutes or by continuous IV infusion.

Patients undergoing BMT: Administer by IV infusion over 4 hours or by continuous IV infusion.

Sub-Q Administration

Dilution

For direct, rapid sub-Q injection, administer undiluted.

Can be diluted with 5% dextrose injection for sub-Q infusion. When filgrastim is 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. Do not dilute to a final concentration of <5 mcg/mL.

Rate of Administration

Patients with chemotherapy-induced neutropenia: Administer by sub-Q injection or continuous sub-Q infusion.

Patients undergoing BMT: Administer by continuous sub-Q infusion.

For mobilization of hematopoietic progenitor cells: Administer by sub-Q injection or continuous sub-Q infusion.

For treatment of congenital, cyclic, or idiopathic neutropenia: Administer by sub-Q injection.

Patients with neutropenia associated with HIV infection: Administer by sub-Q injection.

Dosage

Pediatric Patients

Chemotherapy-induced Neutropenia

IV or Sub-Q

Individualize dosage depending on type and dosage of myelosuppressive chemotherapy. Initially, 5 mcg/kg once daily, administered by sub-Q injection, short (15–30 minutes) IV infusion, or continuous sub-Q or IV infusion, for up to 2 weeks or until the ANC reaches 10,000/mm³ following the expected chemotherapy-induced ANC nadir. Administer the first dose no earlier than 24 hours after administration of chemotherapy. Dosage may be increased in increments of 5 mcg/kg with each chemotherapy cycle, according to the duration and severity of the ANC nadir.

Congenital, Cyclic, and Idiopathic Neutropenias

Congenital Neutropenia

Sub-Q

Initially, 6 mcg/kg administered by sub-Q injection twice daily; individualize dosage according to clinical course and neutrophil count.

Cyclic or Idiopathic Neutropenia

Sub-Q

Initially, 5 mcg/kg administered by sub-Q injection once daily; individualize dosage according to clinical course and neutrophil count.

Neutropenia Associated with HIV Infection and Antiretroviral Therapy

Sub-Q

Adolescents: 5–10 mcg/kg administered by sub-Q injection once daily for 2–4 weeks.†

Adults

Chemotherapy-induced Neutropenia

IV or Sub-Q

Individualize dosage depending on type and dosage of myelosuppressive chemotherapy. Initially, 5 mcg/kg once daily, administered by sub-Q injection, short (15–30 minutes) IV infusion, or continuous sub-Q or IV infusion, for up to 2 weeks or until the ANC reaches 10,000/mm³ following the expected chemotherapy-induced ANC nadir. Administer the first dose no earlier than 24 hours after administration of chemotherapy. Dosage may be increased in increments of 5 mcg/kg with each chemotherapy cycle, according to the duration and severity of the ANC nadir.

Bone Marrow Transplantation

IV or Sub-Q

Initially, 10 mcg/kg daily, administered by IV infusion over 4 or 24 hours or by sub-Q infusion over 24 hours. Administer the first dose ≥24 hours after cytotoxic chemotherapy and ≥24 hours after BMT. Reduce dosage to 5 mcg/kg daily when the ANC is >1000/mm³ for 3 consecutive days. Discontinue filgrastim if the ANC remains >1000/mm³ for an additional 3 consecutive days. If ANC is <1000/mm³ following discontinuance of filgrastim, reinitiate therapy at 5 mcg/kg daily. If ANC is <1000/mm³ at any time when the 5-mcg/kg daily dosage is being used, increase dosage to 10 mcg/kg daily and repeat preceding steps.

Peripheral Blood Progenitor Cell Transplantation

Mobilization of Hematopoietic Progenitor Cells

Sub-Q

10 mcg/kg once daily, administered by sub-Q injection or continuous sub-Q infusion, for 6–7 days. Manufacturer recommends that filgrastim be administered for ≥4 days prior to first leukapheresis and be continued until the last leukapheresis is performed. Modify dosage if the leukocyte count increases to >100,000/mm³.

Administration Following Reinfusion of PBPC Collection

Sub-Q

5–24 mcg/kg daily until a sustainable ANC (≥500/mm³) is attained.

Congenital, Cyclic, and Idiopathic Neutropenias

Congenital Neutropenia

Sub-Q

Initially, 6 mcg/kg administered by sub-Q injection twice daily; individualize dosage according to clinical course and neutrophil count.

Cyclic or Idiopathic Neutropenia

Sub-Q

Initially, 5 mcg/kg administered by sub-Q injection once daily; individualize dosage according to clinical course and neutrophil count.

Myelodysplastic Syndromes andAplastic Anemia

Myelodysplastic Syndromes

IV

Dosages of 50–400 mcg/m² administered once daily by IV infusion over 30 minutes have been uesd.†

Sub-Q

Dosages of 0.3–10 mcg/kg administered once daily by sub-Q injection have been used.†

Neutropenia Associated with HIV Infection and Antiretroviral Therapy

Sub-Q

5–10 mcg/kg administered by sub-Q injection once daily for 2–4 weeks.†

Prescribing Limits

Pediatric Patients

Chemotherapy-induced Neutropenia

Dosages that increase the ANC to >10,000/mm³ may not result in any additional clinical benefit and may increase the risk of excessive leukocytosis.

Adults

Chemotherapy-induced Neutropenia

Dosages that increase the ANC to >10,000/mm³ may not result in any additional clinical benefit and may increase the risk of excessive leukocytosis.

Cautions

Contraindications

• Known hypersensitivity to filgrastim, any ingredient in the formulation, or proteins derived from Escherichia coli.

Warnings/Precautions

Warnings

Splenic Rupture

Splenic rupture (including fatalities) reported rarely following administration of filgrastim in healthy donors (for PBPC collection) and in patients.

Evaluate individuals experiencing left upper abdominal or shoulder tip pain for splenomegaly or splenic rupture.

Respiratory Effects

Adult respiratory distress syndrome (ARDS) reported in neutropenic patients with sepsis receiving filgrastim. Evaluate neutropenic patients receiving filgrastim for the presence of ARDS if fever, lung infiltrates, or respiratory distress develops. If ARDS occurs, provide appropriate treatment for ARDS and discontinue or withhold filgrastim until ARDS has resolved.

Sickle Cell Disease

Severe sickle cell crisis reported in patients with sickle cell disease receiving filgrastim.

Use of filgrastim in patients with sickle cell disease should be limited to experts in the management of this disease and only after careful consideration of potential risks and benefits.

Severe Chronic Neutropenia

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. Safety and efficacy in the treatment of neutropenia caused by other hematopoietic disorders (e.g., MDS) have not been established.

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

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

Sensitivity Reactions

Anaphylactoid and allergic-type reactions (e.g., rash, urticaria, facial edema, wheezing, dyspnea, hypotension, tachycardia) reported rarely; reactions tend to occur within the first 30 minutes following administration and are reported most frequently with IV administration. Symptoms generally resolve after administration of antihistamines, corticosteroids, bronchodilators, and/or epinephrine.

General Precautions

Chemotherapy and Radiation Therapy

Filgrastim therapy may allow use of higher cumulative antineoplastic dosages; possible increased risk of thrombocytopenia, anemia, and nonhematologic adverse effects associated with the chemotherapy regimen.

Safety and efficacy of concomitant radiation therapy or cytotoxic chemotherapy not established. Do not administer filgrastim concomitantly with radiation therapy. Administration during the 24 hours before or after administration of cytotoxic chemotherapy is not recommended. (See Interactions.)

Effect on Malignant Cells

The possibility that filgrastim could act as a growth factor for any tumor type, particularly myeloid malignancies, has not been excluded. Safety in chronic myeloid leukemia (CML) or MDS not established.

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

Excessive Leukocytosis

Marked leukocytosis (leukocyte counts ≥100,000/mm³) reported occasionally. Monitor leukocyte counts to avoid potential complications of excessive leukocytosis. (See Laboratory Monitoring under Cautions.)

Premature Discontinuance

Transient increase in neutrophil count generally occurs 1–2 days following initiation of filgrastim in patients receiving myelosuppressive chemotherapy. Avoid premature discontinuance prior to recovery from the expected chemotherapy-induced ANC nadir.

Immunogenicity

Development of binding antibodies to filgrastim reported in a small proportion of patients receiving the drug; the nature and specificity of these antibodies have not been adequately studied. Possibility exists that an antibody directed against filgrastim could cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia.

Dermatologic Effects

Cutaneous vasculitis reported rarely, principally in patients with severe chronic neutropenia receiving long-term therapy. Symptoms generally develop simultaneously with an increase in ANC and abate when ANC is decreased; many patients are able to continue filgrastim at reduced dosage.

Laboratory Monitoring

Perform CBC and platelet counts prior to initiation of chemotherapy and routinely (twice weekly) during filgrastim therapy for chemotherapy-induced neutropenia.

Perform CBC and platelet counts frequently (3 times weekly) following BMT.

Monitor neutrophil counts after 4 days of therapy for mobilization of PBPC.

In patients with congenital, cyclic, or idiopathic neutropenia, perform CBC and platelet counts twice weekly during the initial 4 weeks of therapy, twice weekly during the first 2 weeks following any dosage adjustment, once monthly during the first year of treatment if the patient is clinically stable, and at least quarterly thereafter if the patient is stable. Annual bone marrow and cytogenic evaluations advised in patients with congenital neutropenia.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether filgrastim is distributed into milk; caution advised.

Pediatric Use

Safety and efficacy not established in neonates or patients with autoimmune neutropenia of infancy.

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). The relationship between these events and filgrastim is unknown.

Adverse effects reported in children with cancer receiving filgrastim are similar to those reported in adults. Alterations in growth and development, sexual maturation, or endocrine function not reported. Possible subclinical splenomegaly.

Geriatric Use

Safety and efficacy profiles similar to those in younger adults receiving filgrastim following myelosuppressive chemotherapy. Clinical studies for other 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.

Common Adverse Effects

Medullary bone pain, nausea, vomiting.

Interactions

Drugs Affecting Platelet Count

Possible decreased platelet counts when used concomitantly with drugs known to decrease the platelet count; use with caution.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following sub-Q injection, with peak serum concentrations generally attained within 4–5 hours.

Distribution

Extent

Rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver.

Not known whether filgrastim distributes into CSF or milk or crosses the placenta in humans.

Elimination

Metabolism

Not known whether filgrastim is metabolized.

Elimination Route

Elimination route is not known. Level of circulating neutrophils may affect filgrastim clearance, with clearance increasing as neutrophil counts increase.

Half-life

About 3.5 hours.

Stability

Storage

Parenteral

2–8°C. May be allowed to reach room temperature for up to 24 hours before use.

Compatibility

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

Parenteral

Solution Compatibility

Drug Compatibility

Actions

• Influences leucopoiesis; affects the proliferation and differentiation of neutrophils within the bone marrow and possibly other sites (e.g., spleen).
• Binds directly to G-CSF-specific high-affinity receptors on neutrophil progenitor target cell surfaces.
• Induces neutrophilia. Stimulates neutrophil proliferation in all stages of granulopoiesis, increases input of precursor cells into the myeloblast compartment, and shortens the time required for neutrophil precursors to mature and appear in circulation.
• Enhances certain end-cell functions of normal mature neutrophils (e.g., phagocytosis, chemotaxis, production of superoxide anions, priming of the cellular metabolism associated with respiratory burst, antibody-dependent cellular cytotoxicity).
• Increases and sustains the ANC throughout administration principally by increasing mature segmented polymorphonuclear granulocytes; however, ANC transiently decreases with each dose.
• May increase lymphocyte and monocyte counts; does not affect eosinophil or basophil counts; does not consistently affect hemoglobin levels or hematocrit; transient dose-dependent decrease in platelet count may occur.
• Reduces duration and severity of neutropenia in patients with chemotherapy-induced neutropenia; ANC nadir occurs sooner and there is accelerated recovery of neutrophil counts.
• Leukocyte differentials usually demonstrate a shift to the left (toward progenitor cells) during therapy; promyelocytes and myeloblasts may be present on the differentials.

Advice to Patients

• Importance of clinicians providing patients adequate oral and written instructions regarding proper administration technique. Importance of providing a copy of the manufacturer’s information for patients or their caregivers.
• Importance of patients not reusing syringes and needles; importance of proper, safe disposal of needles, syringes, and unused drug.
• Importance of recognizing and reporting adverse effects (e.g., sensitivity reactions).
• Importance of adhering to the treatment regimen, including regular monitoring of blood counts.
• Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
• 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.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.