Filgrastim

Not to be confused with granulocyte-macrophage colony-stimulating factor or epoetin alfa.

Filgrastim
Names
Trade namesNeupogen, Zarxio, Granix, others
Other namesfilgrastim-aafi, filgrastim-sndz
IUPAC name
  • Human granulocyte colony stimulating factor
Clinical data
Drug classHematopoietic Agents
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3[1]
  • US: N (Not classified yet)[1]
    Routes of
    use    		IV, subQ
    Defined daily dose0.35 milligram[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa692033
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC845H1343N223O243S9
    Molar mass18802.90 g·mol−1

    Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count.[3] Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause.[3] It may also be used to increase white blood cells for gathering during leukapheresis.[3] It is given either by injection into a vein or under the skin.[3]

    Common side effects include fever, cough, chest pain, joint pain, vomiting, and hair loss.[3] Severe side effects include splenic rupture and allergic reactions.[3] It is unclear if use in pregnancy is safe for the baby.[3] Filgrastim is a recombinant-DNA form of the naturally occurring granulocyte colony-stimulating factor (G-CSF).[3] It works by stimulating the body to increase neutrophil production.[3]

    Filgrastim was approved for medical use in the United States in 1991.[3] It is on the World Health Organization's List of Essential Medicines.[4] The wholesale cost in the developing world is about US$3.95 to US$94.66 per dose.[5][6] In the United Kingdom it cost the NHS about £50.15 per 300 μg dose.[7] In the United States treatment costs more than US$200.[8] Filgrastim biosimilar medications are also available.[3]

    Medical uses

    Filgrastim is used to treat neutropenia,[9] stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation.

    Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis for use in hematopoietic stem cell transplantation.

    Dosage

    The defined daily dose is 0.35 milligrams (by injection).[2]

    Side effects

    The most commonly observed side effect is mild bone pain after repeated administration,[10] and local skin reactions at the site of injection.[11][12] Other observed adverse effects include serious allergic reactions (including a rash over the whole body,[13] shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), ruptured spleen (sometimes resulting in death),[14] alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis.[11] Severe sickle cell crises, in some cases resulting in death, have been associated with the use of filgrastim in patients with sickle cell disorders.[12]

    Interactions

    Drug interactions between filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

    Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results.[12]

    Filgrastim has not been studied in pregnant women and its effects on the fetus is unknown. If taking filgrastim while pregnant, it is possible that traces of the drug could be found in the baby's blood. It is not known if the drug can get into human breast milk.

    Mechanism of action

    Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSF regulates the production of neutrophils within the bone marrow; endogenous G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells.

    G-CSF is a colony stimulating factor which has been shown to have minimal direct in vivo or in vitro effects on the production of other haematopoietic cell types. Neupogen (filgrastim) is the name for recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF).[12]

    Society and culture

    Production

    It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced by E. coli is different from G-CSF naturally made in humans.

    Commercialization

    Filgrastim is marketed under several brand names, including:

    CompanyBrand
    Cadila PharmaceuticalsFilcad
    Abbott LaboratoriesImumax
    Dr. Reddy's LaboratoriesGrafeel
    Intas BiopharmaceuticalsNeukine
    AmgenNeupogen[15][16]
    Emcure PharmaceuticalsEmgrast
    Reliance Life SciencesReligrast
    Novartis/SandozZarzio[17][18] and Zarxio[19]
    BioconNufil
    PfizerNivestim[20][21] and Nivestym[22]

    Apricus Biosciences is currently developing and testing a product under the brand name Nupen which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.

    Biosimilars

    See also: Biosimilars

    In 2015, Sandoz's filgrastim-sndz (trade name Zarxio), obtained the approval of the U.S. Food and Drug Administration (FDA) as a biosimilar.[19][23][24] This was the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), as part of the Affordable Care Act.[19] Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.[24]

    Zarxio is approved for the same indications as Neupogen, and can be prescribed by a health care professional for: patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia.

    — FDA, March 6, 2015

    In 2018, filgrastim-aafi (trade name Nivestym) was approved for use in the United States.[22]

    Neukine is an Indian biosimlar filgrastim and approved for the same indications as of Neupogen. Neukine is manufactured and marketed by Intas Pharmaceuticals Limited at Ahmedabad, India.

    In September 2008, Ratiograstim, Tevagrastim, Biograstim, and Filgrastim ratiopharm were approved for use in the European Union.[25][26][27][28] Filgrastim ratiopharm was withdrawn in July 2011 and Biograstim was withdrawn in December 2016.

    In February 2009, Filgrastim Hexal and Zarzio were approved for use in the European Union.[29][30]

    In June 2010, Nivestim was approved for use in the European Union.[31]

    In October 2013, Grastofil was approved for use in the European Union.[32]

    In September 2014, Accofil was approved for use in the European Union.[33]

    Cost

    Shortly after it was introduced, analyses of whether filgrastim is a cost-effective way of preventing febrile neutropenia depended upon the clinical situation and the financial model used to pay for treatment.[34] The longer-acting pegfilgrastim may in some cases be more cost-effective.[35] The introduction of biosimilars into the market resulted in a price reduction for the original, patent-protected product and increased use.[36]

    See also

    References

    1. 1 2 "Filgrastim Use During Pregnancy". Drugs.com. 13 September 2018. Archived from the original on 18 December 2019. Retrieved 17 December 2019.
    2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 29 October 2020. Retrieved 18 September 2020.
    3. 1 2 3 4 5 6 7 8 9 10 11 "Filgrastim". The American Society of Health-System Pharmacists. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    4. ↑ World Health Organization (2019). "World Health Organization model list of essential medicines: 21st list 2019". World Health Organization (WHO). hdl:10665/325771. {{cite journal}}: Cite journal requires |journal= (help)
    5. ↑ "Filgrastim". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    6. ↑ "Filgrastim- ERC: International Drug Price Indicator Guide". erc.msh.org. Archived from the original on 10 May 2017. Retrieved 19 December 2016.
    7. ↑ British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. p. 678. ISBN 9780857111562.
    8. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 292. ISBN 9781284057560.
    9. ↑ Crawford, J.; Glaspy, J. A.; Stoller, R. G.; Tomita, D. K.; Vincent, M. E.; McGuire, B. W.; Ozer, H. (2005). "Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia". Supportive Cancer Therapy. 3 (1): 36–46. doi:10.3816/SCT.2005.n.023. PMID 18632435.
    10. ↑ Moore DC, Pellegrino AE (September 2017). "Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management". Ann Pharmacother. 51 (9): 797–803. doi:10.1177/1060028017706373. PMID 28423916.
    11. 1 2 Neupogen "Neupogen: Patient Information Leaflet". Amgen. Archived from the original on 10 November 2013. Retrieved 24 June 2013.
    12. 1 2 3 4 "Neupogen- filgrastim injection, solution". DailyMed. 15 November 2019. Archived from the original on 25 November 2020. Retrieved 20 December 2019.
    13. ↑ Scott WR, Silberstein L, Flatley R, Ardeshna KM, Korostoff N, Dawe S (September 2009). "Cutaneous reaction to pegfilgrastim presenting as severe generalized skin eruption". Br. J. Dermatol. 161 (3): 717–9. doi:10.1111/j.1365-2133.2009.09371.x. PMID 19614649.
    14. ↑ Zimmer BM, Berdel WE, Ludwig WD, Notter M, Reufi B, Thiel E (March 1993). "Fatal spleen rupture during induction chemotherapy with rh GM-CSF priming for acute monocytic leukemia. Clinical case report and in vitro studies". Leuk. Res. 17 (3): 277–83. doi:10.1016/0145-2126(93)90012-a. PMID 8450676.
    15. ↑ "Neupogen". U.S. Food and Drug Administration (FDA). Archived from the original on 28 August 2021. Retrieved 20 December 2019.
    16. ↑ "FDA Reviews What Could Be First Biosimilar". Discov. Dev. Mag. Rockaway, New Jersey, United States. Associated Press. 25 July 2014. Archived from the original on 29 July 2014.
    17. ↑ "Zarzio EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 15 October 2019. Retrieved 20 December 2019.
    18. ↑ "Zarzio 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 4 July 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019.
    19. 1 2 3 "FDA approves first biosimilar product Zarxio". U.S. Food and Drug Administration (FDA) (Press release). 6 March 2015. Archived from the original on 11 December 2015. Retrieved 23 November 2015.
    20. ↑ "Nivestim EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 20 December 2019. Retrieved 20 December 2019.
    21. ↑ "Nivestim 12 MU/ 0.2 ml solution for injection/infusion - Summary of Product Characteristics (SmPC)". (emc). 18 December 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019.
    22. 1 2 "Drug Approval Package: Nivestym (filgrastim-aafi)". U.S. Food and Drug Administration (FDA). 21 February 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019.
    23. ↑ "Zarxio (filgrastim-sndz)". U.S. Food and Drug Administration (FDA). 20 April 2015. Archived from the original on 20 December 2019. Retrieved 20 December 2019.
    24. 1 2 Tavernise, Sabrina; Pollack, Andrew (6 March 2015). "F.D.A. Approves Zarxio, Its First Biosimilar Drug". The New York Times. Archived from the original on 23 October 2015. Retrieved 23 November 2015.
    25. ↑ "Ratiograstim EPAR". European Medicines Agency (EMA). Archived from the original on 14 August 2020. Retrieved 2 April 2020.
    26. ↑ "Tevagrastim EPAR". European Medicines Agency (EMA). Archived from the original on 16 October 2019. Retrieved 2 April 2020.
    27. ↑ "Biograstim EPAR". European Medicines Agency (EMA). Archived from the original on 22 October 2020. Retrieved 2 April 2020.
    28. ↑ "Filgrastim ratiopharm EPAR". European Medicines Agency (EMA). Archived from the original on 21 January 2021. Retrieved 2 April 2020.
    29. ↑ "Filgrastim Hexal EPAR". European Medicines Agency (EMA). Archived from the original on 30 December 2019. Retrieved 2 April 2020.
    30. ↑ "Zarzio EPAR". European Medicines Agency (EMA). Archived from the original on 15 October 2019. Retrieved 2 April 2020.
    31. ↑ "Nivestim EPAR". European Medicines Agency (EMA). Archived from the original on 20 December 2019. Retrieved 2 April 2020.
    32. ↑ "Grastofil EPAR". European Medicines Agency (EMA). Archived from the original on 12 November 2020. Retrieved 2 April 2020.
    33. ↑ "Accofil EPAR". European Medicines Agency (EMA). Archived from the original on 23 March 2020. Retrieved 2 April 2020.
    34. ↑ Neymark, Niels (1998). Assessing the Economic Value of Anticancer Therapies. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 215–219. ISBN 978-3-642-72123-6. OCLC 851760173.
    35. ↑ Ellery, Tony (2012). Pharmaceutical lifecycle management : making the most of each and every brand. Hansen, Neal. Hoboken, N.J.: John Wiley & Sons. p. 214. ISBN 978-1-118-26679-3. OCLC 797824835.
    36. ↑ Cornes, Paul. Biosimilars. Bennett, David. Abingdon. p. 54. ISBN 978-1-910797-67-9. OCLC 1064690227. Archived from the original on 28 August 2021. Retrieved 27 June 2020.

    Further reading

    • Santoso, Budiono; van Boxtel, Christoffel Jos; Edwards, Ralph I., eds. (2001). Drug benefits and risks: international textbook of clinical pharmacology. New York: Wiley. ISBN 0-471-89927-5. {{cite book}}: Unknown parameter |name-list-format= ignored (help)
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