TBO-Filgrastim (Granix)

Background

Tbo-filgrastim (Granix), manufactured by Teva, is a recombinant human granulocyte colony-stimulating factor (G-CSF) FDA approved to reduce the duration of severe neutropenia in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy with significant evidence of febrile neutropenia (FN). Granix is not technically considered a biosimilar to Neupogen (filgrastim) because it was filed as a Biologics License Application since a biosimilars approval pathway had not been established at the time of FDA submission. Although these 2 drugs have slight structural differences, the pharmacokinetic parameters, safety, and efficacy between the 2 biologics do not significantly differ.^1,2

Pharmacology/Pharmacokinetics

Granix is a G-CSF produced by recombinant DNA technology that binds to G-CSF receptors in bone marrow to stimulate neutrophil proliferation. Granix also stimulates end-cell functional activation, thereby increasing both neutrophil counts and activity. The absolute bioavailability of Granix, following a 5-mcg/kg subcutaneous (SC) dose in healthy volunteers, is 33%. In cancer patients, the time to achieve a maximum absolute neutrophil count (ANC_max) was 3 to 5 days following administration of Granix, returning to baseline by 21 days after chemotherapy. Median Tmax of Granix is 4 to 6 hours and median half-life of Granix is 3.2 to 3.8 hours.^1,3

Dosing

The recommended dose of Granix is 5 mcg/kg/day administered as an SC injection. Recommended injection sites, which should be regularly rotated, include the abdomen (not within 2 inches of the navel), front of the middle thighs, upper outer area of buttocks, and upper back portion of the arms. The first dose should be administered no earlier than 24 hours after myelosuppressive chemotherapy. Granix should not be administered within 24 hours prior to chemotherapy. Therapy should be continued until the neutrophil count passes nadir and recovers to within normal limits. No dosage adjustment is necessary in patients with mild renal impairment.^1,3

Clinical Efficacy

Three key clinical trials have been published to establish Granix as an equivalent alternative, in terms of efficacy and safety, to Neupogen (filgrastim) in reducing the duration of severe neutropenia and incidence of FN in adults. These studies were carried out in breast cancer, non—small cell lung cancer, and non-Hodgkin lymphoma patients receiving myelotoxic chemotherapy. Each study had similar inclusion criteria of an Eastern Cooperative Oncology Group performance status <2, absolute neutrophil count >1.5 x 10⁹, a platelet count >100 x 10⁹/L, and adequate cardiac, hepatic, and renal function, along with certain criteria for the specific cancer involved in each study.

The studies also had a similar study design in that treatment with either Granix or Neupogen was divided into 4 cycles, each 5 to 14 days in length, and that patients would receive daily injections of either drug, both dosed at 5 mcg/kg/day, starting 1 day after chemotherapy. The primary endpoint, identical in all 3 trials, was duration of severe neutropenia in cycles 1 and 4. Secondary end points, also identical in all 3 studies, were incidence of observed FN and of protocol-defined FN, defined as necessitating administration of systemic antibiotics, across all cycles; depth of ANC nadir in cycles 1 and 4; and time to ANC recovery in cycles 1 and 4.

For safety analysis, investigators found that the adverse events profile, which included bone pain, myalgia, and asthenia, was similar between the Granix and Neupogen groups, and no distinct changes were observed throughout the course of the study for laboratory parameters, physical examination findings, or vital signs. All 3 trials reached the same conclusion, that treatment with Granix is a well-tolerated option in reducing the duration of severe neutropenia and incidence of FN in patients receiving a myelotoxic chemotherapy regimen, with safety and efficacy similar to Neupogen.^4-6

Medication Safety

Tbo-filgrastim (Granix) may be confused with filgrastim as a sound-alike/look-alike drug. Although Granix has no black box warnings, the following potentially severe adverse events may occur with use and warrant immediate discontinuation of the drug: splenic rupture, acute respiratory distress syndrome, sickle crises in patients with sickle cell disease, and serious allergic reactions, including anaphylaxis, on initial exposure.^1,3

Availability and Cost

Granix is available as a single-use, preservative-free, prefilled syringe which may be supplied with or without an UltraSafe Passive Needle Guard. The 2 available strengths are 300 mcg/0.5 mL at an average wholesale price (AWP) of $268.80 and 480 mcg/0.8 mL at an AWP of $459.00. Additional information can be found at www.granixhcp.com.^1,7

Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and a clinical assistant professor at the UNC Eshelman School of Pharmacy. Sandra Hanna is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center.

References

• Granix [package insert]. North Wales, PA: Cephalon, Inc; July 2013.
• Lubenau H, Sveikata A, Gumbrevicius G, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther. 2009;47(4):275-282.
• Granix. Micromedex [online database]: Greenwood Village, CO. December 2013.
• del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau H. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer. 2008;8:332.
• Engert A, Griskevicius L, Zyuzgin Y, Lubenau H, del Giglio A. XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma. 2009;50(3):374-379.
• Gatzemeier U, Ciuleanu T, Dediu M, Ganea-Motan E, Lubenau H, Del Giglio A. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009;4(6):736-740
• Granix. UpToDate [online database]: Indianapolis, IN: Wolters Kluwer Health; 2013. www.uptodate.com.