Efbemalenograstim alfa-vuxw
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
Efbemalenograstim alfa-vuxw is a leukocyte growth factor that is FDA approved for the prevention of incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Recommended Dose: 20 mg administered subcutaneously once per chemotherapy cycle. Administer approximately 24 hours after cytotoxic chemotherapy. Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy.
Dosage Forms and Strengths: Injection: 20 mg/mL solution in a single-dose prefilled syringe.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Efbemalenograstim alfa-vuxw FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
- Patients with a history of serious allergic reactions to granulocyte stimulating factors such as efbemalenograstim alfa-vuxw, pegfilgrastim, or filgrastim products
Warnings
- Splenic Rupture
Splenic rupture, including fatal cases, can occur following the administration of recombinant human granulocyte colony-stimulating factor (rhG CSF) products, such as RYZNEUTA. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving RYZNEUTA.
- Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) can occur in patients receiving rhG-CSF products, such as RYZNEUTA. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving RYZNEUTA for ARDS. Discontinue RYZNEUTA in patients with ARDS.
- Serious Allergic Reactions
Serious allergic reactions, including anaphylaxis, can occur in patients receiving rhG-CSF products, such as RYZNEUTA. Permanently discontinue RYZNEUTA in patients with serious allergic reactions. RYZNEUTA is contraindicated in patients with a history of serious allergic reactions to RYZNEUTA or other rhG-CSF products such as pegfilgrastim, eflapegrastim or filgrastim products.
- 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 RYZNEUTA. Discontinue RYZNEUTA if sickle cell crisis occurs.
- 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 RYZNEUTA.
- Leukocytosis
White blood cell (WBC) counts of 100 × 10 9/L or greater have been observed in patients receiving rhG-CSF products. Monitor complete blood count (CBC) during RYZNEUTA therapy. Discontinue RYZNEUTA treatment if WBC count of 100 × 10 9/L or greater occurs.
- Thrombocytopenia
Thrombocytopenia has been reported in patients receiving rhG-CSF products. Thrombocytopenia occurred in 11% of RYZNEUTA-treated patients. One patient (0.4%) experienced severe thrombocytopenia. Monitor platelet counts.
- 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.
- Potential for Tumor Growth Stimulatory Effects on Malignant Cells
The granulocyte colony-stimulating factor (G-CSF) receptor through which RYZNEUTA acts has been found on tumor cell lines. The possibility that RYZNEUTA acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which RYZNEUTA is not approved, cannot be excluded.
- 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.
- 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 RYZNEUTA if aortitis is suspected.
- Nuclear Imaging
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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
Postmarketing Experience
There is limited information regarding Efbemalenograstim alfa-vuxw Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Efbemalenograstim alfa-vuxw Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Risk Summary Although available data with RYZNEUTA use in pregnant women are insufficient to establish whether there is a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to other human G CSF products. These studies have not established an association of G-CSF product use during pregnancy with major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats and rabbits that received cumulative doses of efbemalenograstim alfa-vuxw approximately 2.6 and 0.7 times, respectively, the recommended human dose (based on body surface area).
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
Three studies were conducted in pregnant rats dosed with efbemalenograstim alfa-vuxw at cumulative doses up to approximately 2.6 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation. No evidence of fetal loss or structural malformations was observed in any study. Growth and learning were also unaffected.
Pregnant rabbits were dosed with efbemalenograstim alfa-vuxw every other day during organogenesis at cumulative doses up to 0.7 times the recommended human dose showed no signs of fetal loss or structural malformations.
Maternal toxicity (decreased weight gain or weight loss and/or death) was observed when higher cumulative doses of efbemalenograstim alfa-vuxw were used in an early dose-ranging study in rabbits.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Efbemalenograstim alfa-vuxw in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Efbemalenograstim alfa-vuxw during labor and delivery.
Nursing Mothers
There are no data on the presence of efbemalenograstim alfa-vuxw or its metabolite in either human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for efbemalenograstim alfa-vuxw and any potential adverse effects on the breastfed child from efbemalenograstim alfa-vuxw or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
Clinical studies of RYZNEUTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with RYZNEUTA has not identified differences in responses between the elderly and younger patients.
Gender
There is no FDA guidance on the use of Efbemalenograstim alfa-vuxw with respect to specific gender populations.
Race
There is no FDA guidance on the use of Efbemalenograstim alfa-vuxw with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Efbemalenograstim alfa-vuxw in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Efbemalenograstim alfa-vuxw in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Efbemalenograstim alfa-vuxw in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Efbemalenograstim alfa-vuxw in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Efbemalenograstim alfa-vuxw Administration in the drug label.
Monitoring
There is limited information regarding Efbemalenograstim alfa-vuxw Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Efbemalenograstim alfa-vuxw and IV administrations.
Overdosage
Overdosage of RYZNEUTA 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
Pharmacology
Efbemalenograstim alfa-vuxw, a leukocyte growth factor, is a 413 amino acid recombinant fusion protein consisting of human G-CSF, a 16 amino-acid linker, and the Fc portion of human IgG2. In solution, efbemalenograstim alfa-vuxw forms covalently-linked dimers (disulfide bonds between Fc moieties), resulting in an immunoglobulin-like structure. The dimer is a water-soluble, glycosylated protein with a molecular weight of approximately 93.4 kilodaltons (kDa), of which 89.5 kDa is attributed to amino acids (protein sequence) and the remainder is from glycosylation. Efbemalenograstim alfa-vuxw is obtained from genetically-engineered strain of Chinese hamster ovary (CHO) cells grown in a serum-free medium.
Mechanism of Action
Efbemalenograstim alfa-vuxw is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
Structure
There is limited information regarding Efbemalenograstim alfa-vuxw Structure in the drug label.
Pharmacodynamics
Over the tested dose range of 30 to 360 μg/kg in healthy adult males, neutrophils generally increased in a dose-dependent manner; however, the effect on neutrophils plateaued at the top two doses of 240 and 360 μg/kg.
In patients with breast cancer given EC chemotherapy, in cycle 1, median ANC peaked on Day 4 (about 24 hours after efbemalenograstim alfa-vuxw administration) for the 240 and 320 μg/kg doses, declined to nadir on Days 8–9, and then recovered to a count of 2.0 × 10 9/L and higher by Day 11. The ANC levels in cycles 2, 3, and 4 tended to be higher than those observed in cycle 1.
In patients with breast cancer given TAC chemotherapy, in cycle 1, median ANC peaked on Day 3 (about 24 hours after efbemalenograstim alfa-vuxw administration) in cycle 1 and 3, reached nadir on Day 8, and recovered to 2.0 x 10 9/L on Days 9 and 10 for the 320 μg/kg and 240 μg/kg doses, respectively. Mean ANC nadir was higher with 320 μg/kg compared to 240 μg/kg in both cycle 1 (0.75 x 10 9/L and 0.29 x 10 9/L, respectively), and cycle 3 (1.19 x 10 9/L and 0.57 x 10 9/L, respectively).
Pharmacokinetics
The pharmacokinetics of efbemalenograstim alfa-vuxw was studied in female patients with breast cancer and healthy male subjects. Efbemalenograstim alfa-vuxw exhibited nonlinear and time-dependent pharmacokinetics over the dose range of 30 to 360 μg/kg. At the approved recommended dose in healthy subjects, the mean (%CV) C maxwas 1202 ng/mL (56%), and the AUC 0-infwas 76357 h*ng/mL (65%). At the approved recommended dose in patients with breast cancer, the geometric mean (CV%) Cmax was 1085 ng/mL (92%) in Cycle 1 and 525 ng/mL (163%) in Cycle 3; the geometric mean (CV%) AUC 0-infwas 54858 h*ng/mL (110%) in Cycle 1 and 26217 h*ng/mL (167%) in Cycle 3.
Absorption
The median tmax of efbemalenograstim alfa-vuxw administered as 80 to 320 μg/kg in female patients with breast cancer receiving EC chemotherapy ranged from 24 hours to 48 hours in Cycle 1 and 9 to 30 hours in Cycle 3. The median t maxof efbemalenograstim alfa-vuxw administered as 240 to 320 μg/kg in female participants with breast cancer receiving TAC chemotherapy was 36 hours in Cycle 1 and ranged from 24 to 30 hours in Cycle 3.
Distribution
The geometric mean (CV%) apparent volume of distribution of efbemalenograstim alfa-vuxw was 18.8 L (257%) in Cycle 1 and 40.7 L (387%) in Cycle 3 in female patients with breast cancer.
Elimination
The geometric mean (CV%) apparent clearance of efbemalenograstim alfa-vuxw was 0.36 L/h (110%) in Cycle 1 and 0.76 L/h (167%) in Cycle 3. The geometric mean (CV%) elimination half-life of efbemalenograstim alfa-vuxw was 35.6 h (108%) in Cycle 1 and 36.9 h (120%) in Cycle 3. Neutrophil receptor binding is an important component of the clearance of efbemalenograstim alfa-vuxw, and serum clearance is directly related to the number of neutrophils.
Metabolism
Efbemalenograstim alfa-vuxw is expected to be metabolized into small peptides by catabolic pathways.
Specific Populations
No clinically significant differences were observed based on age (20 to 83 years) or body weight (40 to 137 kg) [see Use in Specific Populations ( 8.5)]. The impact of sex, race/ethnicity, renal impairment, hepatic impairment, and pregnancy on the pharmacokinetics of efbemalenograstim alfa-vuxw are unknown.
Nonclinical Toxicology
No carcinogenicity or mutagenesis studies have been conducted with efbemalenograstim alfa-vuxw.
Efbemalenograstim alfa did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 2.2 times higher than the recommended human dose (based on body surface area).
Clinical Studies
The efficacy of RYZNEUTA to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs was evaluated in two randomized, controlled studies.
Study GC-627-04 [NCT02872103] was a randomized, double-blind, placebo-controlled study that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m 2administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 122 patients were randomized to receive a single subcutaneous injection of RYZNEUTA (20 mg) or placebo on day 2 of chemotherapy cycle 1. All patients received RYZNEUTA (20 mg) on day 2 of chemotherapy cycles 2 – 4. The patients were 30 to 69 years of age and all female. The race was 99% Caucasian, and 1% Black. The ethnicity was 2% Hispanic or Latino.
Efficacy was based upon the mean duration of severe (Grade 4) neutropenia in cycle 1 which was lower for RYZNEUTA-treated patients as compared to placebo-treated patients (LS mean: 1.4 days versus 4.3 days, respectively, p<0.001 [95% CI: 2.4, 3.5]). The incidence of febrile neutropenia (defined as temperature ≥38.3℃, or >38.0℃ sustained for at least 1 hour, and ANC < 0.5 × 109/L) was also lower for RYZNEUTA-treated patients compared to placebo-treated patients in cycle 1 (4.8% versus 25.6%, respectively, p=0.0016; 20.8% difference [95% CI: 1.8%, 38.8%].
Study GC-627-05 [NCT03252431] was a randomized, active-controlled study that compared RYZNEUTA to pegfilgrastim. Study GC-627-05 employed docetaxel 75 mg/m 2and cyclophosphamide 600 mg/m 2administered every 21 days for up to 4 cycles for the treatment of non-metastatic breast cancer. In this study, 393 patients were randomized to receive a single subcutaneous injection of RYZNEUTA (20 mg) or pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle. The patients were 26 to 83 years of age and all female and Caucasian. The ethnicity was 0.3% Hispanic or Latino.
The study demonstrated that the mean days of severe (Grade 4) neutropenia of RYZNEUTA-treated patients did not exceed that of pegfilgrastim-treated patients by more than 0.6 days in cycle 1 of chemotherapy. The mean days of severe neutropenia in cycle 1 were 0.2 days in both the RYZNEUTA and pegfilgrastim arms (difference in means 0.0 days [95% CI -0.1, 0.1]).
Subgroup analyses of treatment effect were not useful due to small subgroup sizes.
How Supplied
RYZNEUTA (efbemalenograstim alfa-vuxw) injection is supplied in 1 mL prefilled single-dose syringes for manual subcutaneous injection. The prefilled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (20 mg/mL). Each syringe contains 20 mg efbemalenograstim alfa-vuxw in a sterile, clear, colorless, preservative-free solution (pH 5.2) containing acetate (0.6 mg), EDTA (0.29 mg), polysorbate 20 (0.1 mg), sodium (0.23 mg), and sorbitol (50 mg) in Water for Injection, USP.
RYZNEUTA (efbemalenograstim alfa-vuxw) injection is a clear, colorless, preservative-free solution supplied in a prefilled single-dose syringe with a 27-gauge, 1/2-inch needle and an UltraSafe Passive™ Needle Guard, containing 20 mg of efbemalenograstim alfa-vuxw.
Caution: This product contains natural rubber latex which may cause allergic reactions. The needle cap of the prefilled syringe contains natural rubber; persons with latex allergies should not administer this product.
RYZNEUTA is provided in a dispensing pack containing one 20 mg/mL prefilled syringe (NDC 73491-627-01).
RYZNEUTA prefilled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (20 mg/mL) for direct administration to adult patients.
Storage
Store refrigerated at 2° to 8°C (36° to 46°F) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 48 hours. Do not freeze. Discard syringe if frozen.
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information)
Advise patients of the following risks and potential risks with RYZNEUTA:
Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their healthcare provider immediately [see Warnings and Precautions ( 5.1)] . Dyspnea, with or without fever, progressing to acute respiratory distress syndrome, may occur. Advise patients to report dyspnea to their healthcare provider immediately [see Warnings and Precautions ( 5.2)] . Serious allergic reactions may occur, which may be signaled by rash, facial edema, wheezing, dyspnea, hypotension, or tachycardia. Advise patients to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions ( 5.3)] . In patients with sickle cell disease, sickle cell crisis and death have occurred with use of human granulocyte colony-stimulating factors. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of RYZNEUTA [see Warnings and Precautions ( 5.4)] . Glomerulonephritis may occur. Symptoms include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their healthcare provider immediately [see Warnings and Precautions ( 5.5)] . Capillary leak syndrome may occur. Symptoms include hypotension and edema. Advise patients to report signs and symptoms of capillary leak syndrome to their healthcare provider immediately [see Warnings and Precautions ( 5.9)] . There may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive RYZNEUTA in conjunction with chemotherapy and/or radiation therapy. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Advise patients to report to their physician signs and symptoms of MDS/AML [see Warnings and Precautions ( 5.9)] . Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately [see Warnings and Precautions ( 5.11)] . RYZNEUTA ®(efbemalenograstim alfa-vuxw)
Manufactured by:
EVIVE BIOTECHNOLOGY SINGAPORE PTE. LTD. Singapore, 189720
U.S. License No 2248
© 2023 Evive Biotechnology Singapore PTE. LTD.
For more information, go to www.ryzneuta.com or call 1-888-292-9617
Precautions with Alcohol
Alcohol-Efbemalenograstim alfa-vuxw interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
RYZNEUTA ®
Look-Alike Drug Names
There is limited information regarding Efbemalenograstim alfa-vuxw Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.