2.1 Recommended Dosage

The recommended dosage of Rolvedon is a single subcutaneous injection of 13.2 mg administered once per chemotherapy cycle. Administer approximately 24 hours after cytotoxic chemotherapy. Do not administer within the period from 14 days before to 24 hours after administration of cytotoxic chemotherapy.

2.2 Administration

Rolvedon is administered subcutaneously via a single-dose prefilled syringe.

Prior to use‚ take the carton out of the refrigerator and place the sealed blister tray on a clean flat surface for a minimum of 30 minutes to allow the product to reach room temperature. Do not warm up the prefilled syringe in any other way. Discard any prefilled syringe left at room temperature for greater than 12 hours. Do not shake. If Rolvedon is accidentally frozen, do not use. Remove the tray from box and carefully remove the prefilled syringe from the tray. If you drop the prefilled syringe onto a hard surface, do not use it. Use a new syringe for the injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Rolvedon if discoloration or particulates are observed.

Administer the entire contents of the prefilled syringe.

If the patient or caregiver misses a dose of Rolvedon, instruct them to contact their healthcare provider.

The Rolvedon prefilled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (13.2 mg/0.6 mL) for direct administration.

Not made with natural rubber latex.

5.1 Splenic Rupture

Splenic rupture, including fatal cases, can occur following the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) products, such as Rolvedon. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Rolvedon.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) can occur in patients receiving rhG-CSF products, such as Rolvedon. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Rolvedon for ARDS. Discontinue Rolvedon in patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, can occur in patients receiving rhG-CSF products, such as Rolvedon. Permanently discontinue Rolvedon in patients with serious allergic reactions. Rolvedon is contraindicated in patients with a history of serious allergic reactions to eflapegrastim, pegfilgrastim, or filgrastim products [see Contraindications ( 4)].

5.4 Sickle Cell Crisis in Patients with Sickle Cell Disorders

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

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving rhG-CSF products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose-reduction or discontinuation of rhG-CSF. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Rolvedon.

5.6 Leukocytosis

White blood cell (WBC) counts of 100 x 10 9/L or greater have been observed in patients receiving rhG-CSF products. Monitor complete blood count (CBC) during Rolvedon therapy. Discontinue Rolvedon treatment if WBC count of 100 x 10 9/L or greater occurs.

5.7 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving rhG-CSF products. Monitor platelet counts.

5.8 Capillary Leak Syndrome

Capillary leak syndrome has been reported after administration of rhG-CSF products and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency and severity, and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.9 Potential for Tumor Growth Stimulatory Effects on Malignant Cells

The granulocyte colony-stimulating factor (G-CSF) receptor through which Rolvedon acts has been found on tumor cell lines. The possibility that Rolvedon acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which Rolvedon is not approved, cannot be excluded.

5.10 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer

MDS and AML have been associated with the use of rhG-CSF products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.11 Aortitis

Aortitis has been reported in patients receiving rhG-CSF products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Rolvedon if aortitis is suspected.

5.12 Nuclear Imaging

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone imaging results.

6.1 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 Rolvedon was evaluated in Study 1 and Study 2 [see Clinical Studies ( 14)]. Patients with early-stage breast cancer received Rolvedon 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/m 2and cyclophosphamide 600 mg/m 2(TC) chemotherapy.

Among patients receiving Rolvedon, 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. Table 1summarizes the adverse reactions that occurred in Studies 1 and 2.

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

8.1 Pregnancy

Risk Summary

There are no available data on Rolvedon 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.

8.2 Lactation

Risk Summary

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 Rolvedon and any potential adverse effects on the breastfed child from Rolvedon or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 314 patients in clinical studies of Rolvedon, 39% were 65 and over, while 6% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

12.1 Mechanism of Action

Eflapegrastim-xnst is a recombinant human granulocyte growth factor that binds to G-CSF receptors on myeloid progenitor cells and neutrophils, triggering signaling pathways that control cell differentiation, proliferation, migration and survival.

12.2 Pharmacodynamics

Eflapegrastim-xnst has been shown to elevate neutrophil counts in healthy subjects and in cancer patients. Absolute neutrophil count (ANC), C maxand area under the effect curve (AUEC last) increased with increasing doses of eflapegrastim-xnst in a linear, but less than dose-proportional, manner over a dose range of 45 to 350 mcg/kg.

12.3 Pharmacokinetics

The pharmacokinetics of eflapegrastim-xnst was studied in healthy subjects and patients with breast cancer. After subcutaneous (SC) dosing, the pharmacokinetics of eflapegrastim-xnst was nonlinear and exposure increases were not dose-proportional over the dose range of 45 to 350 mcg/kg.

Absorption

The median T maxof eflapegrastim-xnst is 25 hours (6 to 144 hours) in patients with breast cancer following administration of the recommended dosage.

Distribution

The volume of distribution of eflapegrastim-xnst is 1.44 L.

Elimination

The geometric mean half-life of eflapegrastim-xnst in patients with breast cancer is 36.4 hours (Range: 16.1 to 115 hours) during Cycle 1. Eflapegrastim-xnst clearance decreased with increasing doses following single dose administration, suggesting target-mediated clearance of eflapegrastim-xnst by neutrophils. Following repeat administration, clearance increased in Cycle 3 as compared to Cycle 1, potentially due to the subsequent increase in neutrophils. In in vitrostudies, the IgG4 Fc fragment in eflapegrastim-xnst binds to the neonatal Fc receptor (FcRn), facilitating the FcRn-mediated transcytosis of eflapegrastim-xnst.

Metabolism

Eflapegrastim-xnst is expected to be metabolized by endogenous degradation following receptor-mediated internalization by cells bearing the G-CSF receptor.

Excretion

Eflapegrastim-xnst was not detected in urine.

Drug Interaction Studies

No studies evaluating the drug interaction potential of eflapegrastim-xnst have been conducted.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of eflapegrastim-xnst or of other eflapegrastim products.

Antibodies to eflapegrastim-xnst were detected using bridging enzyme-linked immunosorbent assay (ELISA) with a sensitivity of 65 ng/mL. During the 12-week treatment period in the two randomized studies, twenty-one of 297 (7.1%) patients treated with eflapegrastim-xnst developed antibodies. At the 12-month follow-up visit after the last dose of treatment in the two randomized studies, 28 of 297 (9.4%) patients treated with eflapegrastim-xnst developed antibodies.

Neutralizing antibodies were detected by a cell-based assay with a sensitivity of 1.95 mcg/mL. One patient out of 297 (0.3%) in the eflapegrastim-xnst arm tested positive for neutralizing antibodies post-treatment. Treatment-emergent anti-PEG antibodies were detected by a direct binding ELISA in 126 out of 268 patients (47%) treated with eflapegrastim-xnst. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety or effectiveness of Rolvedon over the treatment duration of 12 weeks. There was no identified clinically significant effect of anti-drug antibodies on the safety profile of Rolvedon during the 12-month follow-up period after the last dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.