Pegfilgrastim

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Prefilled Syringe Kit, Subcutaneous [preservative free]:

Neulasta Onpro: 6 mg/0.6 mL (0.6 mL)

Solution, Subcutaneous [preservative free]:

Neulasta: 6 mg/0.6 mL (0.6 mL)

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Fulphila: pegfilgrastim-jmdb 6 mg/0.6 mL (0.6 mL)

Udenyca: pegfilgrastim-cbqv 6 mg/0.6 mL (0.6 mL)

Ziextenzo: pegfilgrastim-bmez 6 mg/0.6 mL (0.6 mL)

Pharmacology

Mechanism of Action

Pegfilgrastim stimulates the production, maturation, and activation of neutrophils and activates neutrophils to increase both their migration and cytotoxicity. Pegfilgrastim has a prolonged duration of effect relative to filgrastim and a reduced renal clearance.

Pharmacokinetics/Pharmacodynamics

Excretion

Primarily through binding to neutrophils

Half-Life Elimination

SubQ: Pediatrics (100 mcg/kg dose): 0 to 5 years: 30.1 ± 38.2 hours; 6 to 11 years: 20.2 ± 11.3 hours; 12 years and older: 21.2 ± 16 hours; Adults: 15 to 80 hours. Pharmacokinetics (in adults) were comparable between manual subcutaneous injection and the On-body injector system.

Use: Labeled Indications

Hematopoietic radiation injury syndrome, acute (Neulasta only): To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Prevention of chemotherapy-induced neutropenia (Neulasta and pegfilgrastim biosimilars): To decrease the incidence of infection (as manifested by febrile neutropenia), in patients with nonmyeloid malignancies receiving myelosuppressive cancer chemotherapy associated with a clinically significant incidence of febrile neutropenia.

Limitation of use: Pegfilgrastim products are not indicated for mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplant.

Note: Fulphila (pegfilgrastim-jmdb), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez) are approved as biosimilars to Neulasta (pegfilgrastim). In Canada, Lapelga is approved as a biosimilar to Neulasta (pegfilgrastim).

Contraindications

Hypersensitivity (serious allergic reaction) to pegfilgrastim, filgrastim, or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to E. coli-derived proteins.

Dosage and Administration

Dosing: Adult

Note: Fulphila (pegfilgrastim-jmdb), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez) are approved as biosimilars to Neulasta (pegfilgrastim). In Canada, Lapelga is approved as a biosimilar to Neulasta (pegfilgrastim).

Prevention of chemotherapy-induced neutropenia (Neulasta and pegfilgrastim biosimilars): SubQ: 6 mg once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy; Note: Do not administer in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Hematopoietic radiation injury syndrome, acute (Neulasta only): SubQ: 6 mg once weekly for 2 doses. Obtain a baseline CBC prior to administration, but do not delay pegfilgrastim use if a CBC is not readily obtainable. Administer the first dose as soon as possible after suspected or confirmed radiation exposure >2 gray (Gy). Administer the second dose 1 week after the first dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chemotherapy-induced neutropenia; prevention: Infants, Children, and Adolescents: Administer once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy. Do not administer in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Note: Direct administration of doses <6 mg using the prefilled syringe is not recommended by the manufacturer (it does not have graduation marks necessary for accurate measurement of doses other than 6 mg). Manufacturer weight-band dosing is comparable to 0.1 mg/kg/dose.

<10 kg: SubQ: 0.1 mg/kg (0.01 mL/kg)

10 to 20 kg: SubQ: 1.5 mg (0.15 mL)

21 to 30 kg: SubQ: 2.5 mg (0.25 mL)

31 to <45 kg: SubQ: 4 mg (0.4 mL)

≥45 kg: SubQ: 6 mg (0.6 mL)

Hematopoietic radiation injury syndrome (acute): Infants, Children, and Adolescents: Obtain a baseline CBC prior to administration, but do not delay pegfilgrastim use if a CBC is not readily obtainable. Administer 2 doses; the first dose as soon as possible after suspected or confirmed radiation exposure greater than 2 gray (Gy) and administer the second dose 1 week after the first dose. Note: Direct administration of doses <6 mg using the prefilled syringe is not recommended by the manufacturer (it does not have graduation marks necessary for accurate measurement of doses other than 6 mg). Manufacturer weight-band dosing is comparable to 0.1 mg/kg/dose.

<10 kg: SubQ: 0.1 mg/kg (0.01 mL/kg)

10 to 20 kg: SubQ: 1.5 mg (0.15 mL)

21 to 30 kg: SubQ: 2.5 mg (0.25 mL)

31 to <45 kg: SubQ: 4 mg (0.4 mL)

≥45 kg: SubQ: 6 mg (0.6 mL)

Reconstitution

Subcutaneous administration from the prefilled syringe: For doses of 6 mg, the prefilled syringe may be used. Direct administration of doses <6 mg using the prefilled syringe is not recommended by the manufacturers (do not have graduation marks necessary for accurate measurement of doses other than 6 mg).

On-body injector (Neulasta): A health care provider must fill the On-body injector (OBI) prior to applying to the patient's skin. The OBI delivery system may be applied on the same day as chemotherapy administration as long as pegfilgrastim is delivered no less than 24 hours after chemotherapy is administered.

The prefilled syringe provided in the OBI kit contains overfill to compensate for loss during delivery; do not use for manual subcutaneous injection (will result in higher than recommended dose). Do not use prefilled syringe intended for manual injection to fill the OBI; may result in lower than intended dose. The OBI has not been studied for use in pediatrics.

Administration

SubQ: Administer subcutaneously. Do not use 6 mg fixed dose in infants, children, or adolescents <45 kg (ASCO [Smith 2006]). Pegfilgrastim products are available in prefilled syringes for manual subcutaneous administration or as a kit for use with the On-body injector (OBI) (Neulasta). Direct administration of doses <6 mg using the prefilled syringe is not recommended by the manufacturer (it does not have graduation marks necessary for accurate measurement of doses other than 6 mg); use caution to avoid dosing errors.

Manual subcutaneous administration: Administer to outer upper arms, abdomen (except within 2 inches of navel), front middle thigh, or upper outer buttocks. Allow prefilled syringe to reach room temperature for at least 30 minutes prior to injection. Engage/activate needle guard following use to prevent accidental needlesticks.

On-body injector (Neulasta): A health care provider must fill the OBI prior to applying to the patient’s skin. Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor OBI injection status). The OBI system will deliver pegfilgrastim over ~45 minutes approximately 27 hours after application. The OBI delivery system may be applied on the same day as chemotherapy administration as long as pegfilgrastim is delivered at least 24 hours after chemotherapy is administered. Keep the OBI dry for ~3 hours before dose delivery. Do not use additional materials to hold OBI in place; this could dislodge the cannula and result in a missed or incomplete dose. Provide patient training and instruct patients to notify health care provider immediately if OBI malfunctions or did not perform as intended (may require a replacement dose). A missed dose may occur if the OBI fails or leaks; if a dose is missed, administer a new dose by manual subcutaneous injection as soon as possible after discovery of missed dose. Do not expose the OBI to oxygen-rich environments (eg, hyperbaric chambers), MRI, x-ray (including airport x-ray), CT-scan, ultrasound, or radiation treatment (may damage injector system). Keep the OBI at least 4 inches away from electrical equipment, including cell phones, cordless phones, microwaves, and other common appliances (injector may not work properly). The OBI is not recommended for use in patients with acute hematopoietic radiation injury syndrome. The OBI has not been studied in pediatric patients. Refer to prescribing information for further details.

The prefilled syringe provided in the OBI kit contains overfill to compensate for loss during delivery; do not use for manual subcutaneous injection (will result in higher than recommended dose). Do not use prefilled syringe intended for manual injection to fill the OBI; may result in lower than intended dose. The OBI is only for use with pegfilgrastim; do not use to deliver other medications.

Storage

Store under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. If syringe for manual injection is inadvertently frozen, allow to thaw in refrigerator; discard if frozen more than one time. Protect from light. Do not shake. Allow prefilled syringe to reach room temperature for ≥30 minutes prior to injection; discard if kept at room temperature for>48 hours (Neulasta, Udenyca) or 72 hours (Fulphila, Ziextenzo). The On-body injector kit (Neulasta) should be kept refrigerated until 30 minutes prior to use and should not be held at room temperature for >12 hours prior to use (discard if stored at room temperature for >12 hours).

Drug Interactions

Belotecan: Granulocyte Colony-Stimulating Factors may enhance the neutropenic effect of Belotecan. Consider therapy modification

Bleomycin: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of bleomycin. Consider therapy modification

Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

Tisagenlecleucel: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Tisagenlecleucel. Avoid combination

Topotecan: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Topotecan. Specifically, the risk for the development of interstitial lung disease may be increased. Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of topotecan. Additionally, monitor patients closely for the development of interstitial lung disease with this combination. Consider therapy modification

Test Interactions

May interfere with bone imaging studies; increased hematopoietic activity of the bone marrow may appear as transient positive bone imaging changes

Adverse Reactions

Adverse reaction incidences based on studies including concomitant docetaxel therapy.

>10%: Neuromuscular & skeletal: Ostealgia (31%)

1% to 10%: Neuromuscular & skeletal: Limb pain (9%)

<1%, postmarketing, and/or case reports: Acute respiratory distress syndrome, anaphylaxis, antibody development, capillary leak syndrome, erythema of skin, flushing, glomerulonephritis, hypersensitivity angiitis, injection site reaction, leukocytosis, local inflammation (aortitis), pulmonary alveolar hemorrhage, severe hypersensitivity, sickle cell crisis, skin rash, splenic rupture, splenomegaly, Sweet's syndrome, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Aortitis: Aortitis has been reported in patients receiving pegfilgrastim; aortitis may occur as early as the first week after treatment initiation. Manifestations of aortitis may include generalized fever, abdominal pain, malaise, back pain, and increased inflammatory markers (eg, c-reactive protein, WBC count). Consider aortitis in patients who develop related signs/symptoms of unknown etiology. Discontinue pegfilgrastim if aortitis is suspected.
• Capillary leak syndrome: Capillary leak syndrome (CLS), characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration, may occur in patients receiving human granulocyte colony-stimulating factors (G-CSF), including pegfilgrastim products. CLS episodes vary in frequency and severity. If CLS develops, monitor closely and manage symptomatically (may require intensive care). CLS may be life-threatening if treatment is delayed.
• Hypersensitivity: Hypersensitivity, including serious allergic reactions or anaphylaxis may occur, usually with the initial dose; may recur within days after discontinuation of initial antiallergic treatment. Permanently discontinue for serious allergic reactions. Do not administer in patients with a history of serious allergic reaction to pegfilgrastim or filgrastim products. Skin rash, urticaria, generalized erythema, and flushing have been reported.
• Nephrotoxicity: Glomerulonephritis has occurred, and generally resolved after pegfilgrastim dose reduction or discontinuation. Diagnosis was made by the presence of azotemia, microscopic and macroscopic hematuria, proteinuria, and renal biopsy. Evaluate if glomerulonephritis is suspected; if felt due to pegfilgrastim products, consider dose reduction or therapy interruption.
• Hematologic effects: Leukocytosis (WBC ≥100,000/mm³) has been reported in patients receiving pegfilgrastim products. Monitor complete blood counts during therapy.
• Respiratory distress syndrome: Acute respiratory distress syndrome (ARDS) has been reported with use; evaluate patients with pulmonary symptoms such as fever, pulmonary infiltrates, or respiratory distress for ARDS. Discontinue pegfilgrastim products if ARDS occurs.
• Splenic rupture: Rare cases of splenic rupture have been reported (some fatal); evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal pain or shoulder pain.

Disease-related concerns:

• Sickle cell disease: Severe and sometimes fatal sickle cell crises may occur in patients with sickle cell disorders receiving pegfilgrastim products. Discontinue if sickle cell crisis occurs.

Concurrent drug therapy issues:

• Cytotoxic chemotherapy: Do not use pegfilgrastim products in the period 14 days before to 24 hours after administration of cytotoxic chemotherapy because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. Safety and efficacy have not been established with dose-dense chemotherapy regimens (ASCO [Smith 2006]).

Special populations:

• Elderly patients: The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update recommend that prophylactic colony-stimulating factors be used in patients ≥65 years with diffuse aggressive lymphoma treated with curative chemotherapy (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), especially if patients have comorbid conditions (ASCO [Smith 2015]).
• Pediatric patients: The 6 mg fixed dose should not be used in infants, children, and adolescents weighing <45 kg. Colony-stimulating factor (CSF) use in pediatric patients is typically directed by clinical pediatric protocols. The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update states that CSFs may be reasonable as primary prophylaxis in pediatric patients when chemotherapy regimens with a high likelihood of febrile neutropenia are employed. Likewise, secondary CSF prophylaxis should be limited to high-risk patients. In pediatric cancers in which dose-intense chemotherapy (with a survival benefit) is used, CSFs should be given to facilitate chemotherapy administration. CSFs should not be used in the pediatric population for non-relapsed acute lymphoblastic or myeloid leukemia when no infection is present (ASCO [Smith 2015]). The On-body injector has not been studied for use in pediatrics.

Dosage form specific issues:

• Acrylic: Some products may contain acrylic adhesive; patients sensitive to acrylic adhesives may experience a significant reaction.
• Latex: The packaging (needle cover) may contain latex.
• On-body injector (Neulasta): The On-body injector (OBI) is not recommended for use in patients with acute hematopoietic radiation injury syndrome. The OBI contains an acrylic adhesive; may result in a significant reaction in patients who react to acrylic adhesives. A health care provider must fill the OBI prior to applying to the patient's skin. The OBI delivery system may be applied on the same day as chemotherapy administration as long as pegfilgrastim is delivered no less than 24 hours after chemotherapy is administered. The prefilled syringe provided in the OBI kit contains overfill to compensate for loss during delivery; do not use for manual subcutaneous injection (will result in higher than recommended dose). Do not use prefilled syringe intended for manual injection to fill the OBI; may result in lower than intended dose. The OBI is only for use with pegfilgrastim; do not use to deliver other medications. Do not expose the OBI to oxygen-rich environments (eg, hyperbaric chambers); MRI; x-ray (including airport x-ray); CT scan; or ultrasound (may damage injector system). Keep the OBI at least 4 inches away from electrical equipment, including cell phones, cordless phones, microwaves, and other common appliances (injector may not work properly). Missed or partial doses have been reported; the risk for neutropenia, neutropenic fever, and/or infection is increased if a dose is not correctly delivered. Provide patient training and instruct patients to notify health care provider immediately if OBI malfunctions or did not perform as intended.

Other warnings/precautions:

• Appropriate use: Colony-stimulating factors may be considered in cancer patients with febrile neutropenia who are at high risk for infection-associated complications or who have prognostic factors indicative of a poor clinical outcome (eg, prolonged and severe neutropenia, age >65 years, hypotension, pneumonia, sepsis syndrome, presence of invasive fungal infection, uncontrolled primary disease, hospitalization at the time of fever development) (ASCO [Smith 2006]; IDSA [Freifeld 2011]). Colony-stimulating factors should not be routinely used for patients with neutropenia who are afebrile. Dose-dense regimens that require colony-stimulating factors should only be used within the context of a clinical trial or if supported by convincing evidence. The safety/efficacy of pegfilgrastim in the setting of dose-dense therapy has not been fully established (ASCO [Smith 2015]).
• Nuclear imaging: Increased bone marrow hematopoietic activity due to colony-stimulating factor use has been associated with transient positive bone-imaging changes; interpret results accordingly.
• Tumor growth factor: The G-CSF receptor through which pegfilgrastim (and filgrastim) work has been located on tumor cell lines. Pegfilgrastim may potentially act as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia (pegfilgrastim is not approved for myeloid malignancies).

Monitoring Parameters

Chemotherapy-induced neutropenia: Complete blood count (with differential) and platelet count should be obtained prior to chemotherapy and as clinically necessary.

Hematopoietic radiation injury syndrome: CBC at baseline (do not delay administration if CBC not readily available); estimate absorbed radiation dose.

Evaluate fever, pulmonary infiltrates, and respiratory distress; evaluate for left upper abdominal pain, shoulder tip pain, or splenomegaly. Monitor for signs/symptoms of allergic reactions, aortitis, glomerulonephritis (azotemia, hematuria, proteinuria), and capillary leak syndrome (hypotension, hypoalbuminemia, edema and hemoconcentration). Monitor for sickle cell crisis (in patients with sickle cell anemia).

On-body injector: Monitor for evidence of device malfunction.

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to lower the chance of getting an infection in people with bone marrow problems caused by chemo.
• It is used in patients who have been exposed to certain doses of radiation.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Injection site irritation, redness, or bruising
• Bone pain
• Muscle pain
• Painful extremities

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Dark urine
• Fast heartbeat
• Sweating a lot
• Fast breathing
• Edema
• Upper abdominal pain
• Left shoulder pain
• Abdominal pain
• Back pain
• Injection site pain or bleeding
• Capillary leak syndrome like abnormal heartbeat; chest pain; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; unable to pass urine or change in amount of urine passed; or blood in the urine.
• Dizziness
• Passing out
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.