Filgrastim

Article Author:
Blessing Aghedo
Article Editor:
Vikas Gupta
Updated:
7/6/2020 4:52:24 PM
PubMed Link:
Filgrastim

Indications

Filgrastim was approved in the US in 1991 and is the originator short-acting recombinant methionyl human G-CSF.[1] It has since remained in use with long-acting versions (pegfilgrastim) and biosimilars increasingly being made since the originator approval with similar indications.[2][3][2] This article focuses on the originator filgrastim.

FDA indications 

  1. Reduction of the incidence of infection manifested by febrile neutropenia in patients receiving myelosuppressive chemotherapy.[1]  
  2. Minimizing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML.[4]  
  3. Shortening the duration of neutropenia and neutropenia-related clinical sequelae in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation.[5]
  4. To mobilize hematopoietic progenitor cells to the peripheral blood for collection by leukapheresis in patients undergoing peripheral blood progenitor cell collection and therapy.[6]
  5. Chronic administration to lower the incidence and duration of the sequelae of neutropenia in patients with severe chronic neutropenia.[7]
  6. Reduction of the duration and severity of neutropenia in patients with radiation-induced myelosuppression following a radiological/nuclear incident (hematopoietic syndrome of acute radiation syndrome, or H-ARS).[8] - This was the only indication where only animal trials were conducted due to ethical and feasibility considerations.

Non-FDA indications 

  • Alcoholic hepatitis[9]
  • Anemia in myelodysplastic patients[10]
  • Neutropenia in HIV patients[11]
  • Neutropenia in kidney transplant recipients[12]
  • Neutropenia in hepatitis C patients undergoing treatment[13] 
  • Clozapine induced neutropenia[14]

Mechanism of Action

Filgrastim is a recombinant human methionyl granulocyte colony-stimulating factor(G-CSF) which stimulates the proliferation, maturation of neutrophil progenitors, and functional end-cell activation. It also facilitates their release into the blood.[15] 

Filgrastim exhibits nonlinear pharmacokinetics with a short half-life of 3.5 hours, with filgrastim concentration and neutrophil count being the determinants of clearance.[16] The kidneys clear the drug.

The bioavailability of filgrastim after subcutaneous administration is 60 to 70%. 

Administration

Filgrastim is available as a clear colorless preservative clear liquid in single-dose vials(300 mcg/ml or 480 mcg/1.6ml) or single-dose prefilled syringes(300 mcg/0.5ml or 480 mcg/0.8ml) which is administered subcutaneously or intravenously. 

IV compatibility: 

  • Compatible: 5% dextrose; 5% glucose; 5% dextrose plus albumin (human); 5% glucose plus albumin (human)
  • Incompatible: Saline 

It should NOT be administered 24 hours before and after receiving cytotoxic chemotherapy. Safety and efficacy of the simultaneous use of filgrastim and cytotoxic chemotherapy have not undergone evaluation. 

In cancer patients receiving myelosuppression therapy/adults with AML-  

Recommended starting dose is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes) ‚ or by continuous SC or IV infusion.  

Doses can be titrated by 5 mcg/kg/day for each chemotherapy cycle, depending on the duration and severity of cytotoxicity. 

The recommendation is to administer filgrastim for up to 2 weeks or until ANC is 10000/mm^3. Discontinue drug if ANC>10000/mm^3.[17]

Patients with non-myeloid malignancies undergoing myeloablative therapy following Bone Marrow Transplantation (BMT): Starting dose is 10 mcg/kg via short IV infusion (over 15 to 30 minutes) or continuous IV infusion administered at least 24hrs after BMT or cytotoxic chemotherapy. Dosage adjustment for neutrophil recovery Following BMT via short IV infusion (over 15 to 30 minutes) or continuous IV infusion: 

  • When ANC >1000/mm^3 for 3 consecutive days: reduce to 5 mcg/kg/day  
  • If ANC >1000/mm^3 for an additional 3 or more consecutive days: Discontinue this drug. 
  • Then if, ANC < 1000/mm^3: resume at 5 mcg/kg/day  

If ANC <1000/mm3 while receiving 5 mcg/kg/day: Increase to 10 mcg/kg and repeat the above dose adjustment steps.  

Patients undergoing Peripheral Blood Progenitor Collection(PBPC) and therapy

The recommended dose of filgrastim for the mobilization of PBPC is 10 mcg/kg/day subcutaneously‚ either as a bolus or a continuous infusion.  

The recommendation is to give filgrastim for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. 

Patients with Severe Chronic Neutropenia 

Confirm diagnosis before starting treatment. 

Congenital Neutropenia:

  • The recommended starting dose is 6 mcg/kg BID via subcutaneous injection.

Cyclic/Idiopathic Neutropenia:

  • Recommended starting dose is 5 mcg/kg once a day  

 In the severe chronic neutropenia post-marketing surveillance study, the median daily dose was:

  • Congenital neutropenia: 6mcg/kg
  • Cyclic neutropenia: 2.1 mcg/kg 
  • Idiopathic neutropenia: 1.2 mcg/kg 

Doses administered via subcutaneous injection  

Patients with Radiation-Induced Neutropenia

  • 10 mcg/kg via subcutaneous injection once a day.

Pediatric and Pregnant Female population-

Pharmacokinetics in pediatric patients after chemotherapy is the same as adults with weight-based adjusted doses. There are safety and efficacy studies that have been conducted on the severe chronic neutropenia and PBPC population, revealing no significant adverse effects. 

The drug is pregnancy category C. There are very few studies evaluating the efficacy and safety of the drug in pregnant women. Observational studies reported no association between filgrastim use and pregnancy outcomes, neonatal complications, or infections. The clinician should weigh the benefits and risks before administering the drug to these patients.[7][18]

Adverse Effects

Bone pain is the most commonly reported adverse effect of filgrastim. 

A systematic literature review by Dale et al. reported bone pain and other musculoskeletal symptoms as being the most common adverse effect of filgrastim while also noting the incidence of other adverse effects that were not as significant in comparison.[15] 

The various adverse reactions noted in clinical trials that can occur in the different subsets of patients for which filgrastim is indicated for include:

  • Cancer patients receiving myelosuppressive therapy - Arthralgia, back pain, bone pain, nausea, chest pain, fatigue, pyrexia, dizziness, cough, dyspnea, rash, thrombocytopenia, elevated LDH, elevated alkaline phosphatase. 
  • AML patients receiving induction/consolidation chemotherapy - Back pain, pain in extremity, erythema, maculopapular rash, epistaxis. In patients with sequelae of underlying malignancy/ cytotoxic chemotherapy- Diarrhea, constipation, transfusion reaction. 
  • Patients with non-myeloid malignancies undergoing myeloablative therapy following Bone Marrow Transplantation (BMT) - Rash, hypersensitivity. In patients receiving intensive chemotherapy followed by autologous BMT - hypertension, sepsis, bronchitis, insomnia, anemia, thrombocytopenia.  
  • Patients undergoing peripheral blood progenitor collection and therapy- Headache, bone pain, pyrexia, elevated alkaline phosphatase. 
  • Patients with severe chronic neutropenia - arthralgia, back pain, bone pain, muscle spasms, pain in extremity, chest pain, diarrhea, alopecia, epistaxis, hypoesthesia, splenomegaly, anemia
    • Although total infection rates were significantly lower in filgrastim treated patients, the incidence of upper respiratory tract infection and urinary tract infections was higher compared to placebo. 

Other adverse effects reported since filgrastim's approval are as follows-

  • Aortitis[19]
  • Capillary leak syndrome[20]
  • Cutaneous vasculitis[21]
  • Decreased bone density/Osteoporosis[22]
  • Glomerulonephritis[23]
  • Leukocytosis[24]
  • Pulmonary toxicity - ARDS, alveolar hemorrhage/Hemoptysis[25]
  • Severe allergic reactions including anaphylaxis[26]
  • Sickle Cell disorders - severe sickle cell crisis has been reported in some filgrastim-treated sickle cell patients[27]
  • Splenomegaly/Splenic rupture - Filgrastim-treated patients with symptoms of abdominal pain, especially LUQ, require evaluation. [28]
  • Sweet syndrome [29]

There is limited data on the incidence or frequency of these adverse effects. There have been a few reports of incidence of acute myelogenous leukemia (AML) and/or myelodysplastic syndrome in certain populations receiving filgrastim, especially patients with congenital neutropenia. The Severe Chronic Neutropenia International Registry published a 10-year report in 2003 on the incidence of AML/myelodysplastic syndrome occurring in 35 of 387 patients with congenital neutropenia, but no established no relationship to dose and duration of filgrastim.[7]

Contraindications

Filgrastim is contraindicated in patients with allergic reactions to E. coli-derived proteins, filgrastim, or any component of the product.

Monitoring

The recommended starting dosage is usually 5mcg/kg or 10mcg/kg, depending on the indication, as noted earlier. There has been very limited data regarding the maximum tolerable dosage of filgrastim. Although rare, doses of up to and even greater than 100 mcg/kg have been used in individuals with minimal toxic effects.[7]

Some studies noted a plateau in dose-response curves when the dosage exceeded 10 mcg/kg in bone marrow transplant patients. 

Baseline CBC and platelet counts should be obtained prior to administration and following filgrastim administration.

The following are the required monitoring parameters:

  • Twice weekly in cancer patients on myelosuppressive therapy or AML patients receiving induction/consolidation therapy.
  • Frequently in bone marrow transplant patients.
  • After four days of filgrastim initiation in patients undergoing PBPC collection and discontinued if neutrophil count >100,000/mm^3.
  • During the initial four weeks of filgrastim therapy and the two weeks following any adjustment in the dose in patients with severe chronic neutropenia
    • When a patient is clinically stable, counts should be monitored monthly in the first year and less frequently thereafter. 
  • Every three days until ANC>1000/mm^3 for three consecutive CBCs in patients acutely exposed to myelosuppressive radiation doses.

It is advised not to use filgrastim with concurrent chemotherapy and radiotherapy due to a lack of safety and efficacy studies. 

Toxicity

There is minimal data regarding the maximum tolerable dosage. Adverse effects that occur with filgrastim use mainly resolve following discontinuation of the drug. Some are manageable with supportive measures e.g., bone pain, which is a common side effect usually managed with analgesics. Monitoring is essential to track response and minimize complications.

Although rare(<5%), Leukocytosis with WBC >100,000/mm^3 has been observed in BMT patients with minimal adverse effects. The recommendation is to discontinue the drug if it occurs to prevent potential complications. 

There is no antidote for reversal of filgrastim. 

Enhancing Healthcare Team Outcomes

Filgrastim requires an interprofessional healthcare team approach, including clinicians, nurses, and pharmacists. Although it has uses in other fields of medicine, its primary use is in the field of hematology and oncology for reducing the duration of neutropenia in cancer patients undergoing chemotherapy or patients with myelosuppression. Clinicians should prioritize monitoring patients as monitoring is essential to track the response and minimize complications. Nurses should be aware of the proper way of drug administration and be alert to signs of infection and adverse effects. Pharmacists are also crucial for appropriate dosing schedules. The principal aim of filgrastim is to reduce the incidence of infection manifested by febrile neutropenia in patients receiving myelosuppressive chemotherapy. Thus, being alert to signs of infection would guide dosage and improve response outcomes in these patients. [Level 5] 


References

[1] Crawford J,Ozer H,Stoller R,Johnson D,Lyman G,Tabbara I,Kris M,Grous J,Picozzi V,Rausch G, Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. The New England journal of medicine. 1991 Jul 18;     [PubMed PMID: 1711156]
[2] Castagna L,Bramanti S,Levis A,Michieli MG,Anastasia A,Mazza R,Giordano L,Sarina B,Todisco E,Gregorini AI,Santoro A, Pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support. Annals of oncology : official journal of the European Society for Medical Oncology. 2010 Jul;     [PubMed PMID: 20007996]
[3] Cioch M,Jawniak D,Kotwica K,Wach M,Mańko J,Gorący A,Klimek P,Mazurkiewicz E,Jarosz P,Hus M, Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation. Transplantation proceedings. 2014 Oct;     [PubMed PMID: 25380941]
[4] Heil G,Hoelzer D,Sanz MA,Lechner K,Liu Yin JA,Papa G,Noens L,Szer J,Ganser A,O'Brien C,Matcham J,Barge A, A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood. 1997 Dec 15;     [PubMed PMID: 9389686]
[5] Sheridan WP,Morstyn G,Wolf M,Dodds A,Lusk J,Maher D,Layton JE,Green MD,Souza L,Fox RM, Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet (London, England). 1989 Oct 14;     [PubMed PMID: 2477656]
[6] Schmitz N,Linch DC,Dreger P,Goldstone AH,Boogaerts MA,Ferrant A,Demuynck HM,Link H,Zander A,Barge A, Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet (London, England). 1996 Feb 10;     [PubMed PMID: 8598700]
[7] Dale DC,Cottle TE,Fier CJ,Bolyard AA,Bonilla MA,Boxer LA,Cham B,Freedman MH,Kannourakis G,Kinsey SE,Davis R,Scarlata D,Schwinzer B,Zeidler C,Welte K, Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. American journal of hematology. 2003 Feb;     [PubMed PMID: 12555210]
[8] MacVittie TJ,Bennett AW,Farese AM,Taylor-Howell C,Smith CP,Gibbs AM,Prado K,Jackson W 3rd, The Effect of Radiation Dose and Variation in Neupogen® Initiation Schedule on the Mitigation of Myelosuppression during the Concomitant GI-ARS and H-ARS in a Nonhuman Primate Model of High-dose Exposure with Marrow Sparing. Health physics. 2015 Nov;     [PubMed PMID: 26425903]
[9] Spahr L,Lambert JF,Rubbia-Brandt L,Chalandon Y,Frossard JL,Giostra E,Hadengue A, Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology (Baltimore, Md.). 2008 Jul;     [PubMed PMID: 18537187]
[10] Li E,Lobaina E, Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations. Journal of managed care     [PubMed PMID: 29172978]
[11] Kuritzkes DR, Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus disease: the role of granulocyte colony-stimulating factor. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2000 Feb;     [PubMed PMID: 10671324]
[12] Poon T,Guerra CM, Evaluation of Filgrastim Therapy in Kidney Transplant Recipients. Progress in transplantation (Aliso Viejo, Calif.). 2017 Dec;     [PubMed PMID: 29187137]
[13] Sharvadze L,Karchava M,Bolokadze N,Gatserelia L,Tsertsvadze T, Safety and efficacy of systematic administration of Filgrastim to prevent neutropenia and infections in patient with hepatitis C. Georgian medical news. 2009 Oct;     [PubMed PMID: 19893121]
[14] Friedman J,Yeboah E,Hermenau M, Addition of Filgrastim (Neupogen) for Clozapine Rechallenge in the Case of Parkinson Disease Patient. Clinical neuropharmacology. 2017 Sep/Oct     [PubMed PMID: 28922288]
[15] Dale DC,Crawford J,Klippel Z,Reiner M,Osslund T,Fan E,Morrow PK,Allcott K,Lyman GH, A systematic literature review of the efficacy, effectiveness, and safety of filgrastim. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2018 Jan;     [PubMed PMID: 28939926]
[16] Petros WP,Rabinowitz J,Stuart A,Peters WP, Clinical pharmacology of filgrastim following high-dose chemotherapy and autologous bone marrow transplantation. Clinical cancer research : an official journal of the American Association for Cancer Research. 1997 May;     [PubMed PMID: 9815739]
[17] Cornes P,Gascon P,Chan S,Hameed K,Mitchell CR,Field P,Latymer M,Arantes LH Jr, Systematic Review and Meta-analysis of Short- versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia. Advances in therapy. 2018 Nov;     [PubMed PMID: 30298233]
[18] Behfar M,Faghihi-Kashani S,Hosseini AS,Ghavamzadeh A,Hamidieh AA, Long-Term Safety of Short-Term Administration of Filgrastim (rhG-CSF) and Leukophresis Procedure in Healthy Children: Application of Peripheral Blood Stem Cell Collection in Pediatric Donors. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018 Apr;     [PubMed PMID: 29284143]
[19] Hoshina H,Takei H, Granulocyte-colony stimulating factor-associated aortitis in a woman with advanced breast cancer: a case report and review of the literature. BMC cancer. 2019 Dec 16;     [PubMed PMID: 31842789]
[20] Rechner I,Brito-Babapulle F,Fielden J, Systemic capillary leak syndrome after granulocyte colony-stimulating factor (G-CSF). The hematology journal : the official journal of the European Haematology Association. 2003;     [PubMed PMID: 12692521]
[21] Jain KK, Cutaneous vasculitis associated with granulocyte colony-stimulating factor. Journal of the American Academy of Dermatology. 1994 Aug;     [PubMed PMID: 7518847]
[22] Dale DC,Bolyard AA,Schwinzer BG,Pracht G,Bonilla MA,Boxer L,Freedman MH,Donadieu J,Kannourakis G,Alter BP,Cham BP,Winkelstein J,Kinsey SE,Zeidler C,Welte K, The Severe Chronic Neutropenia International Registry: 10-Year Follow-up Report. Supportive cancer therapy. 2006 Jul 1;     [PubMed PMID: 18632498]
[23] Nasilowska-Adamska B,Perkowska-Ptasinska A,Tomaszewska A,Serwacka A,Marianska B, Acute glomerulonephritis in a donor as a side effect of allogeneic peripheral blood stem cell mobilization with granulocyte colony-stimulating factor. International journal of hematology. 2010 Dec;     [PubMed PMID: 21120643]
[24] Chan K,Farooq R, Hyperleucocytosis following G-CSF treatment for sulfasalazine-induced agranulocytosis. BMJ case reports. 2015 Jul 15;     [PubMed PMID: 26178004]
[25] Arimura K,Inoue H,Kukita T,Matsushita K,Akimot M,Kawamata N,Yamaguchi A,Kawada H,Ozak A,Arima N,Te C, Acute lung Injury in a healthy donor during mobilization of peripheral blood stem cells using granulocyte-colony stimulating factor alone. Haematologica. 2005 Mar;     [PubMed PMID: 15753051]
[26] Doval D,Choudhary D,Sharma SK,Khandelwal V, Severe hypersensitivity allergic reaction to filgrastim in a healthy stem cell donor. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2019 Dec;     [PubMed PMID: 31203715]
[27] Fitzhugh CD,Hsieh MM,Bolan CD,Saenz C,Tisdale JF, Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy. 2009;     [PubMed PMID: 19513902]
[28] Nuamah NM,Goker H,Kilic YA,Dagmoura H,Cakmak A, Spontaneous splenic rupture in a healthy allogeneic donor of peripheral-blood stem cell following the administration of granulocyte colony-stimulating factor (g-csf). A case report and review of the literature. Haematologica. 2006 May;     [PubMed PMID: 16709516]
[29] White JM,Mufti GJ,Salisbury JR,du Vivier AW, Cutaneous manifestations of granulocyte colony-stimulating factor. Clinical and experimental dermatology. 2006 Mar;     [PubMed PMID: 16487091]