On July 20, 2018, Pfizer Inc announced the FDA approval of filgrastim-aafi (Nivestym), a biosimilar to Amgen’s biologic Neupogen (filgrastim). Pharmaceutical biologics are large molecular products created from live organisms that enable targeted therapy for chronic illnesses. Because of their complexity, biologics undergo a unique approval process through the FDA.

Biosimilars are designed to have similar properties as an existing biologic but are not, however, exact copies of their reference biologic product. FDA approval is assessed based on totality of evidence, comparing pharmacokinetic and efficiency data within the relevant patient population.

Indications

The following indications for filgrastim-aafi are approved by the FDA:
  • To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
  • For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML)
  • To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation
  • For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
  • For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia
MECHANISM OF ACTION
Filgrastim-aafi is a granulocyte colony-stimulating factor (G-CSF) created through recombinant DNA technology. Colony-stimulating factors act on hematopoietic cells by binding to receptors and stimulating proliferation. G-CSFs affect the production of neutrophils within the bone marrow.

DOSAGE AND ADMINISTRATION
Filgrastim-aafi is available in the following strengths and dosage forms:

VIAL
  • Injection: 300 μg/mL in a single-dose vial
  • Injection: 480.0 μg/1.6 mL in a single- dose vial
PREFILLED SYRINGE
  • Injection: 300.0 μg/0.5 mL in a single-dose prefilled syringe
  • Injection: 480.0 μg/0.8 mL in a single- dose prefilled syringe
The recommended dosages are listed below.
  • Patients with cancer receiving myelosuppressive chemotherapy or induction and/ or consolidation chemotherapy for AML: 5 μg/kg/day as a single daily subcutaneous injection, by short intravenous (IV) infusion over 15 to 30 minutes, or by continuous IV infusion. Therapy should begin at least 24 hours after chemotherapy and should not be administered within 24 hours prior to chemotherapy. Patients should be monitored twice a week during therapy. The dose can be increased by 5 μg/kg for each chemotherapy cycle if needed. Therapy should be continued for up to 2 weeks post chemotherapy or until the absolute neutrophil count increases to 10,000/mm3.
  • Patients with cancer undergoing bone marrow transplantation: 10 μg/kg/day as an IV infusion no longer than 24 hours. The first dose should be administered at least 24 hours after chemotherapy and bone marrow infusion. Patient monitoring of complete blood counts (CBCs), including platelet counts, should be performed frequently post marrow transplantation. The dose should be titrated as follows:
° Absolute neutrophil count (ANC) >1000/mm3 for 3 consecutive days: Reduce dose to 5 μg/kg/day.
° ANC >1000/mm3 for 3 more consecutive days: Discontinue therapy.
° ANC <1000/mm3: Resume dose at 5 μg/kg/day.
  • Patients undergoing autologous peripheral blood progenitor cell collection and therapy: 10 μg/kg/day as a subcutaneous injection for at least 4 days before the first leukapheresis procedure, continuing until the last leukapheresis. The optimal duration has not been established, but administration for 6 to 7 days with leukapheresis on days 5, 6, and 7 has been shown to be safe and effective. Neutrophil counts should be monitored after 4 days, and therapy should be discontinued if white blood cell count increases to 100,000/mm3.
  • Patients with severe chronic neutropenia: Daily administration is required. Doses should be individualized based on clinical outcomes and ANC. CBCs with differential and platelet counts should be monitored monthly during the first year of treatment.
° Congenital neutropenia: 6 μg/kg as a twice-daily subcutaneous injection
° Idiopathic or cyclic neutropenia: 5 μg/kg as a single-daily subcutaneous injection

WARNINGS AND PRECAUTIONS
Adverse effects that have been reported in some patients following administration of filgrastim include:
  • Splenic rupture
  • Acute respiratory distress syndrome
  • Serious allergic reactions
  • Sickle cell disorders
  • Glomerulonephritis
  • Alveolar hemorrhage and hemoptysis
  • Capillary leak syndrome
  • Severe chronic neutropenia
  • Thrombocytopenia
  • Leukocytosis
  • Cutaneous vasculitis
  • Potential effect on malignant cells
  • Aortitis
CLINICAL STUDIES
Patients with cancer receiving myelosuppressive chemotherapy
The safety and efficacy of filgrastim-aafi was established in a randomized, double-blind, placebo-controlled trial conducted in patients with small cell lung cancer. Patients received up to 6 cycles of IV chemotherapy given on days 1, 2, and 3 of a 21-day cycle, followed by filgrastim-aafi or placebo. Patients receiving filgrastim-aafi were dosed at 4 to 8 μg/kg/day and received a daily subcutaneous injection beginning on day 4 of each cycle for a maximum of 14 days. Of the patients treated with filgrastim-aafi, 40% experienced febrile neutropenia compared with 76% in the placebo group. This was a clinically significant result (P <.001). Additional significant reductions were noticed in the duration of infection, the severity of neutropenia, the incidence and duration of hospital admissions, and the number of reported days of antibiotic use.

Patients with AML receiving induction or consolidation chemotherapy
The safety and efficacy of filgrastim-aafi was established in a randomized, double-blind, placebo-controlled, multicenter trial in patients with newly diagnosed de novo AML. Patients received 5 μg/kg/day subcutaneously of filgrastim-aafi beginning 24 hours after their last chemotherapy dose and continuing until neutrophil recovery (ANC 31000/mm3 for 3 consecutive days or 310,000/mm3 for 1 day) or for a maximum of 35 days. Patients treated with filgrastim-aafi experienced severe neutropenia for a median of 14 days versus 19 days in the placebo group, which was a clinically significant difference (P = .0001). There was also a reduction in median duration of IV antibiotic use (15.0 vs 18.5 days) and median duration of hospitalization (20 days vs 25 days). No statistically significant difference was noted for complete remission rate, median time to progression, or median overall survival.

Patients with cancer undergoing bone marrow transplantation
The safety and efficacy of filgrastim-aafi in reducing the duration of neutropenia in patients undergoing autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of statistically significant reduction in the median number of days of severe neutropenia (trial 1, P = .004; trial 2, P <.001). The number of days of febrile neutropenia was also significantly reduced in trial 2 (P <.0001). The safety and efficacy of filgrastim-aafi in patients undergoing allogenic bone marrow transplantation was evaluated in a randomized placebo-controlled trial. A statistically significant reduction in the median number of days of severe neutropenia was shown (P <.001). Additionally, time to recovery of ANC to 3500/mm3 was shown (P <.001).

Patients undergoing autologous peripheral blood progenitor cell collection and therapy
The safety and efficacy of filgrastim-aafi was supported through noncontrolled tri- als and a randomized trial. The randomized, unblinded study of patients with Hodgkin disease or non-Hodgkin lymphoma undergoing chemotherapy showed significantly fewer days of platelet transfusions in patients who received filgrastim-mobilized peripheral blood progenitor cells compared with autologous bone marrow (6 vs 10 days).

Patients with severe chronic neutropenia
The safety and efficacy of filgrastim-aafi was established in a randomized controlled trial for patients with severe neutropenia. Subcutaneous filgrastim was administered in doses determined by the category of neutropenia (idiopathic, 3.6 μg/kg/day; cyclic, 6 μg/kg/day; congenital, 6 μg/kg/day divided 2 times per day). Doses were incrementally increased to 12 μg/kg/day divided into 2 doses if no response was shown. Patients who received filgrastim showed a lower incidence of infection and fever and duration of fever; decreased days of antibiotic use; and lower incidence, duration, and severity of oropharyngeal ulcers.

Reference

Nivestym (filgrastim-aafi) [prescribing information]. New York; NY: Pfizer Inc; 2018. https://bit.ly/2JMOq9Y. Accessed August 2, 2018.