Neupogen (filgrastim)

Filgrastim is a biosynthetic (recombinant DNA origin) hematopoietic agent (human granulocyte colony-stimulating factor (G-CSF)) that principally affects the proliferation and differentiation of neutrophils within the bone marrow and possibly other sites (e.g., spleen).

Filgrastim and tbo-filgrastim are structurally and pharmacologically similar drugs that contain a related drug substance. Tbo-filgrastim was licensed by the US Food and Drug Administration (FDA) through a biologics license application (BLA), not as a biosimilar to filgrastim; at the time of tbo-filgrastim's submission for approval, FDA had not finalized a process for approving biosimilars.

Filgrastim-sndz, filgrastim-aafi, filgrastim-ayow, and filgrastim-txid are biosimilar to filgrastim (Neupogen(R)). The FDA defines a biosimilar as 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. The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies (e.g., human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity assessment, additional comparative clinical studies).

Therefore, biosimilarity of 2 drugs may be established even when there are formulation or minor structural differences or minor differences in rates of adverse effects between the drugs as long as these differences are not clinically meaningful. Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biological and the reference biological but does not independently establish safety and effectiveness of the proposed biological. In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating that the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alternation or switch.

Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. None of the currently available filgrastim biosimilars have interchangeable data at this time.

In this monograph, unless otherwise stated, the term ''filgrastim products'' refers to filgrastim (the reference drug); tbo-filgrastim; filgrastim-sndz, filgrastim-aafi, filgrastim-ayow, and filgrastim-txid (the biosimilars), or all products.

Filgrastim, tbo-filgrastim, and biosimilars are hematopoietic agents that principally influence leukopoiesis. The drugs appear to elicit the same pharmacologic effects produced by endogenous human granulocyte colony-stimulating factor (G-CSF). Endogenous G-CSF, a growth factor, is a lineage-restricted CSF that principally affects the proliferation, differentiation, and activation of committed progenitor cells of the neutrophil-granulocyte lineage.

In addition, endogenous G-CSF enhances certain functions of mature neutrophils, including phagocytosis, chemotaxis, and antibody-dependent cellular cytotoxicity (ADCC).

Like endogenous G-CSF, filgrastim, tbo-filgrastim, and biosimilars appear to act directly on neutrophil progenitor target cells (granulocyte colony-forming units (CFU-G)) by binding to G-CSF receptors on their cell surfaces. How this binding to receptors results in the various intracellular events necessary to affect proliferation, differentiation, and cell function has not been fully elucidated to date.

Following subcutaneous or IV administration of filgrastim in patients with cancer chemotherapy-induced neutropenia, there is an initial (within 5-60 minutes) decrease in the absolute neutrophil count (ANC) to below baseline levels. Within 1-4 hours after administration, however, the neutrophil count begins to increase rapidly and generally exceeds baseline levels within 24 hours. The initial decrease in neutrophil count may occur because of margination of neutrophils to blood vessel walls, and the subsequent increase may occur as the result of demargination and mobilization of mature neutrophils from the bone marrow and/or other tissues.

The increase in neutrophil count in response to filgrastim generally is dose dependent. Following discontinuance of the drug in patients with chemotherapy-induced neutropenia, a 50% decrease in the ANC generally occurs within 24 hours and the ANC returns to pretreatment levels within 1-7 days.

In healthy individuals, the increase in ANC is sustained throughout the period of filgrastim administration, although transient decreases generally continue to be observed with each dose. In patients with chemotherapy-induced neutropenia, filgrastim reduces the duration and severity of neutropenia but generally does not eliminate the ANC nadir. In a study in patients with small cell lung cancer receiving myelosuppressive chemotherapy, the ANC nadir persisted for 10-15 days in patients not receiving filgrastim but for only 2-3 days in those receiving the drug.

Filgrastim cannot increase neutrophil counts in the absence of progenitor target cells capable of responding to the drug, and the magnitude of the neutrophil response depends on the absolute numbers of target cells available. Patients who previously have received prolonged chemotherapy or excessive radiation generally are less responsive to filgrastim than those who have not received such treatment. Studies in patients with chemotherapy-induced neutropenia and patients with cyclic neutropenia or myelodysplastic syndromes receiving filgrastim indicate that the time to neutrophil response and the percentage of patients responding to the drug are not age dependent since geriatric patients (those 65 years of age or older) appear to respond the same as younger adults.

Results of in vitro studies evaluating the neutrophils produced in response to filgrastim therapy indicate that these cells have a normal survival time and function normally, at least in terms of phagocytic activity and chemotaxis. Neutrophils harvested from patients with various cancers (e.g., small cell lung carcinoma, transitional cell carcinoma of the urothelium) receiving filgrastim are at least as functionally active as those harvested from healthy individuals not receiving the drug.

Filgrastim exhibits nonlinear pharmacokinetics. The drug is rapidly absorbed following subcutaneous injection, and peak serum concentrations of the drug generally are attained within 4-5 hours following rapid subcutaneous injection. Rapid subcutaneous injection of a single 3.45- or 11.5-mcg/kg dose of filgrastim results in peak serum concentrations averaging 4 or 49 ng/mL, respectively, within 2-8 hours; serum concentrations of the drug exceed 10 ng/mL for 8-16 hours after a single subcutaneous dose of 10 mcg/kg or more.

Most of the drug is absorbed through zero-order processes presumably through the lymphatic system. The absolute bioavailability of filgrastim after subcutaneous administration is 60-70%.

Following subcutaneous administration of tbo-filgrastim 5 mcg/kg in patients with cancer, the median time to peak plasma concentrations of the drug was approximately 4-6 hours; no evidence of accumulation was observed with repeated dosing. The absolute bioavailability of tbo-filgrastim following subcutaneous injection of a dose of 5 mcg/kg in healthy individuals is approximately 33%.

Filgrastim is rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver. The volume of distribution of filgrastim following a single IV or subcutaneous dose reportedly averages 150 mL/kg (range: 46-384 mL/kg) in both healthy individuals and patients with cancer. It is not known whether filgrastim is distributed into cerebrospinal fluid.

There is published literature documenting transfer of filgrastim into human milk. There have been reports of transplacental passage of filgrastim products in pregnant women when administered within 30 hours of preterm delivery.

Filgrastim is eliminated by both renal elimination and specific degradation by G-CSF receptors and neutrophil elastase. Clearance is dependent on filgrastim concentration and neutrophil count; G-CSF receptor-mediated clearance is saturated by high concentrations of filgrastim and is diminished by neutropenia.

Some data indicate that serum filgrastim concentrations decline in a biphasic manner following single IV doses. In a limited number of adults with various malignancies, the distribution half-life of filgrastim has ranged from 0.13-1.1 hours and the terminal elimination half-life has ranged from 1.8-7.2 hours. It has been proposed that clearance is initially mediated by the binding of filgrastim to G-CSF receptors.

When filgrastim binding sites become saturated, clearance of filgrastim decreases and elimination then occurs mostly via renal elimination. The manufacturer states that the elimination half-life of filgrastim following subcutaneous or IV administration averages 3.5 hours (range: 0.77-8.5 hours) in healthy individuals or patients with cancer and that the half-life of the drug following a single parenteral dose is comparable to that reported following IV doses of the drug given once daily for 2 weeks.

The median elimination half-life of tbo-filgrastim in patients with cancer receiving chemotherapy is 3.2-3.8 hours; in healthy individuals, median half-life of the drug was approximately 8.9 hours.

Various filgrastim biosimilars are available. Biosimilarity of these products has been demonstrated for the indications described in the table below (See Table 1.)

Generic name: filgrastim
Pronunciation: (fil-GRA-stim)
Drug class: Leukocyte Stimulating Factors
Therapeutic class: Hematological Agents

The following indications are listed for Neupogen:

• Chemotherapy-Induced Neutropenia
• Congenital Neutropenia
• Cyclic Neutropenia
• Hematopoietic Syndrome Of Acute Radiation Syndrome
• Idiopathic Neutropenia
• Neutropenia Secondary To Aml Treatment
• Peripheral Mobilization Of Hematopoietic Stem Cells
• Prevention Of Neutropenia From Cancer Chemotherapy
• Severe Chronic Neutropenia

Also known as: Bone Marrow Syndrome Of Acute Radiation Syndrome, Congenital Aleukia, Congenital Leukopenia, Infantile Genetic Agranulocytosis, Kostmann Neutropenia, Kostmann Syndrome, Neutropenia Due To Acute Myelocytic Leukemia Treatment, Neutropenia Of Unknown Origin, Neutrophilic Leukocytopenia From Cancer Chemotherapy, Neutrophilic Leukopenia From Cancer Chemotherapy, Neutrophilopenia From Cancer Chemotherapy, Patient With Acute Exposure To Myelosuppressive Dose Of Radiation, Periodic Neutropenia, Primary Neutropenia.