Eflapegrastim

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving rhG-CSF products, such as eflapegrastim. Discontinue eflapegrastim if sickle cell crisis occurs.

Risk Summary

There are no available data on eflapegrastim use in pregnant women; however, data from published studies with use of other recombinant human granulocyte colony-stimulating factor (rhG-CSF) products in pregnant women have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Animal reproduction studies were conducted in rats and rabbits. In rats, eflapegrastim-xnst did not adversely affect embryofetal and/or postnatal development when administered from organogenesis throughout lactation at doses that produced maternal exposures up to 7 times the exposure at the recommended clinical dose. In rabbits, eflapegrastim-xnst caused embryofetal lethality and reduced fetal weight when administered during the organogenesis period at approximately 6 times the exposure at the clinical dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryofetal developmental study in rabbits, eflapegrastim-xnst was administered subcutaneously every other day during the period of organogenesis at doses up to 10 times the clinical exposure at the maximum recommended dose of 13.2 mg. Increased post-implantation loss, reduced number of live fetuses, and reduced fetal body weights were observed at 6 times the clinical exposure, based on AUC. No malformations were observed up to 10 times the clinical exposure, based on AUC.

In an embryofetal developmental study in rats, eflapegrastim-xnst administered subcutaneously every other day during the period of organogenesis did not adversely affect embryofetal development at doses up to 7 times clinical exposure, based on AUC.

In a pre- and post-natal development study in rats, eflapegrastim-xnst administered subcutaneously once weekly from organogenesis through lactation did not adversely affect behavioral, developmental, or reproductive parameters at doses up to 7 times the clinical exposure, based on AUC.

There are no data on the presence of eflapegrastim-xnst in human milk, the effects on the breastfed child, or the effects on milk production. Endogenous granulocyte colony-stimulating factor (G-CSF) is present in human milk. Other recombinant human granulocyte colony-stimulating factor (rhG-CSF) products are present in human milk at low levels and are not orally absorbed by infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for eflapegrastim and any potential adverse effects on the breastfed child from eflapegrastim or from the underlying maternal condition.

No long-term carcinogenicity studies have been performed with eflapegrastim-xnst.

Eflapegrastim-xnst was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), Chinese hamster ovary cells chromosomal aberration, rat bone marrow micronucleus).

Eflapegrastim-xnst did not affect reproductive performance or fertility in male or female rats at weekly doses up to 7 times the clinical exposure at the maximum recommended dose of 13.2 mg.

• Splenic rupture
• Acute respiratory distress syndrome
• Serious allergic reactions
• Sickle cell crisis in patients with sickle cell disorders
• Glomerulonephritis
• Leukocytosis
• Thrombocytopenia
• Capillary leak syndrome
• Potential for tumor growth stimulatory effects on malignant cells
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer
• Aortitis
• Nuclear Imaging

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of eflapegrastim was evaluated in Study 1 and Study 2. Patients with early-stage breast cancer received eflapegrastim 13.2 mg by subcutaneous injection (n=314) or pegfilgrastim 6 mg by subcutaneous injection (n=326) on Day 2 of each cycle after docetaxel 75 mg/m² and cyclophosphamide 600 mg/m² (TC) chemotherapy.

Among patients receiving eflapegrastim, a total of 272 patients received four 21-day treatment cycles. The most common adverse reactions (≥20%) were fatigue, nausea, diarrhea, bone pain, headache, pyrexia, anemia, rash, myalgia, arthralgia, and back pain. The following table summarizes the adverse reactions that occurred in Studies 1 and 2.

Common Adverse Reactions with a Frequency of ≥10% Through Week 14 in Patients with Early-Stage Breast Cancer in Study 1 and Study 2:

^* Grouped Terms
^** Study 1 and Study 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the eflapegrastim and the pegfilgrastim treatment groups.

Permanent discontinuation due to an adverse reaction occurred in 4% of patients who received eflapegrastim. The adverse reaction requiring permanent discontinuation in 3 patients who received eflapegrastim was rash.