Rolvedon (eflapegrastim-xnst): Uses, Dosage, Side Effects & Warnings

Uses

Rolvedon is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. Limitations of Use Rolvedon is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. Rolvedon is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. ( 1 ) Limitations of Use Rolvedon is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. ( 1 )

Dosage and administration

• Recommended Dose: 13.2 mg administered subcutaneously once per chemotherapy cycle. ( 2.1 )
• 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. ( 2.1 ) 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 72 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.

Dosage forms and strengths

Injection: 13.2 mg/0.6 mL as a clear, colorless, preservative-free solution in a single-dose prefilled syringe. Injection: 13.2 mg/0.6 mL solution in a single-dose prefilled syringe. ( 3 )

Contraindications

Rolvedon is contraindicated in patients with a history of serious allergic reactions to eflapegrastim, pegfilgrastim, or filgrastim products. Reactions may include anaphylaxis [see Warnings and Precautions ( 5.3 )] . Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as eflapegrastim, pegfilgrastim or filgrastim products. ( 4 )

Warnings and precautions

• Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. ( 5.1 )
• Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Rolvedon in patients with ARDS. ( 5.2 )
• Serious allergic reactions, including anaphylaxis: Permanently discontinue Rolvedon in patients with serious allergic reactions. ( 5.3 )
• Sickle Cell Crisis in Patients with Sickle Cell Disorders: Discontinue Rolvedon if sickle cell crisis occurs. ( 5.4 )
• Glomerulonephritis: Evaluate and consider dose-reduction or interruption of Rolvedon if causality is likely. ( 5.5 )
• Leukocytosis: Monitor complete blood count (CBC) during Rolvedon therapy. ( 5.6 )
• Thrombocytopenia: Monitor platelet counts. ( 5.7 )
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Rolvedon in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.10 ) 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.

Side effects

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
• Splenic rupture [see Warnings and Precautions ( 5.1 )]
• Acute respiratory distress syndrome [see Warnings and Precautions ( 5.2 )]
• Serious allergic reactions [see Warnings and Precautions ( 5.3 )]
• Sickle cell crisis in patients with sickle cell disorders [see Warnings and Precautions ( 5.4 )]
• Glomerulonephritis [see Warnings and Precautions ( 5.5 )]
• Leukocytosis [see Warnings and Precautions ( 5.6 )]
• Thrombocytopenia [see Warnings and Precautions ( 5.7 )]
• Capillary leak syndrome [see Warnings and Precautions ( 5.8 )]
• Potential for tumor growth stimulatory effects on malignant cells [see Warnings and Precautions ( 5.9 )]
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer [see Warnings and Precautions ( 5.10 )]
• Aortitis [see Warnings and Precautions ( 5.11 )]
• Nuclear Imaging [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (≥20%) are fatigue, nausea, diarrhea, bone pain, headache, pyrexia, anemia, rash, myalgia, arthralgia, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-888-713-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 2 and 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 1 summarizes the adverse reactions that occurred in Studies 1 and 2. Table 1. Common Adverse Reactions with a Frequency of ≥10% Through Week 14 in Patients with Early-Stage Breast Cancer in Study 1 and Study 2 Adverse Reaction Rolvedon (N = 314) % Pegfilgrastim** (N=326) % *Grouped Terms **Study 1 and Study 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the Rolvedon and the pegfilgrastim treatment groups. Fatigue * 181 (58%) 192 (59%) Nausea 162 (52%) 166 (51%) Diarrhea 125 (40%) 126 (39%) Bone pain 119 (38%) 121 (37%) Headache * 92 (29%) 90 (28%) Pyrexia * 87 (28%) 84 (26%) Anemia * 77 (25%) 52 (16%) Rash * 77 (25%) 99 (30%) Myalgia 69 (22%) 49 (15%) Arthralgia 66 (21%) 48 (15%) Back pain * 63 (20%) 55 (17%) Decreased appetite 61 (19%) 50 (15%) Peripheral edema * 57 (18%) 53 (16%) Abdominal pain * 53 (17%) 67 (21%) Dizziness * 50 (16%) 38 (12%) Dyspnea * 49 (16%) 44 (13%) Cough * 48 (15%) 51 (16%) Thrombocytopenia * 44 (14%) 17 (5%) Pain 37 (12%) 42 (13%) Pain in extremity 36 (11%) 42 (13%) Local administration reactions * 34 (11%) 27 (8%) Flushing 32 (10%) 27 (8%) 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.

Use in specific populations

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.

Pregnancy

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.

Pediatric use

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Geriatric use

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.

Overdosage

Overdose of Rolvedon may result in leukocytosis and bone pain. In the event of overdose, general supportive measures should be instituted as necessary. Monitor the patient for adverse reactions [see Adverse Reactions ( 6 )] .

Description

Eflapegrastim-xnst is a granulocyte colony-stimulating factor (G‑CSF) produced by covalent coupling of a human G-CSF analog (18.6 kDa) and an Fc fragment of human immunoglobulin G4 (IgG4) (49.8 kDa), both derived from recombinant E. coli , via a single 3.4 kDa polyethylene glycol linker. The recombinant G-CSF domain in eflapegrastim-xnst is a variant of human G-CSF with two serine substitutions at positions 17 and 65, and no additional N-terminal methionine. Eflapegrastim-xnst has a molecular weight of approximately 72 kDa. Rolvedon (eflapegrastim-xnst) injection is a sterile, preservative-free, clear, colorless solution supplied in a single-dose prefilled syringe for subcutaneous use. Each 0.6 mL single-dose prefilled syringe contains 13.2 mg of eflapegrastim-xnst, citric acid monohydrate (2.52 mg), mannitol (30 mg), polysorbate 80 (0.72 mg) and sodium chloride (5.26 mg) in Water for Injection. Sodium hydroxide may be used to adjust pH to 5.5 during manufacturing.

Mechanism of action

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.

How supplied

Rolvedon (eflapegrastim-xnst) injection is a clear, colorless solution supplied in a single-dose prefilled syringe containing 13.2 mg of eflapegrastim-xnst in 0.6 mL solution, with 29-gauge 1/2 inch pre-attached (staked) needle with a needle guard. Rolvedon is provided in a dispensing pack containing one sterile 13.2 mg/0.6 mL prefilled syringe (NDC 76961‑101-01). Store refrigerated at 36°F to 46°F (2°C to 8°C) in the carton to protect from light. Do not shake. Discard any prefilled syringe left at room temperature for greater than 72 hours. Do not freeze; discard syringe if frozen.

Patient information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients to contact their healthcare provider with any questions. Advise patients of the following risks and potential risks with Rolvedon:
• Splenic rupture and splenomegaly [see Warnings and Precautions ( 5.1 )]
• Acute respiratory distress syndrome [see Warnings and Precautions ( 5.2 )]
• Serious allergic reactions [see Warnings and Precautions ( 5.3 )]
• Sickle cell crisis [see Warnings and Precautions ( 5.4 )]
• Glomerulonephritis [see Warnings and Precautions ( 5.5 )]
• Leukocytosis [see Warnings and Precautions ( 5.6 )]
• Thrombocytopenia [see Warnings and Precautions ( 5.7 )]
• Capillary leak syndrome [see Warnings and Precautions ( 5.8 )]
• Potential for tumor growth stimulatory effects on malignant cells [see Warnings and Precautions ( 5.9 )]
• Increased risk of myelodysplastic syndrome and/or acute myeloid leukemia in patients with breast and lung cancer who receive Rolvedon in conjunction with chemotherapy and/or radiation therapy [see Warnings and Precautions ( 5.10 )]
• Aortitis [see Warnings and Precautions ( 5.11 )] Instruct patients who self-administer Rolvedon using the single-dose prefilled syringe of the:
• Importance of following the Instructions for Use
• Dangers of reusing syringes
• Importance of following local requirements for proper disposal of used syringes. Manufactured by: Spectrum Pharmaceuticals, Inc. Lake Forest, IL 60045 U.S. License No. 2312

Active ingredients

Eflapegrastim in 2 products

Rolvedon NDC products (2)

NDC	Strength & form	Labeler	Type
82497-132	Eflapegrastim 13.2 mg/.6mL Injection, Solution	Assertio Specialty Pharmaceuticals, LLC	BLA
76961-101	Eflapegrastim 13.2 mg/.6mL Injection, Solution	Spectrum Pharmaceuticals, Inc.	BLA

Frequently asked questions

What is Rolvedon used for?

Rolvedon is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. Limitations of Use Rolvedon is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell…

What are the side effects of Rolvedon?

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic rupture [see Warnings and Precautions ( 5.1 )] • Acute respiratory distress syndrome [see Warnings and Precautions ( 5.2 )] • Serious allergic reactions [see Warnings and Precautions ( 5.3 )] • Sickle cell crisis in patients with sickle cell disorders [see Warnings… See the full label for the complete list.

Who makes Rolvedon?

Rolvedon is listed by 2 labelers in the FDA NDC directory, including Assertio Specialty Pharmaceuticals, LLC, Spectrum Pharmaceuticals, Inc..