Continuing Education Activity

Pegfilgrastim is a pegylated granulocyte colony-stimulating factor approved by the FDA to reduce the risk of febrile neutropenia in patients receiving myelosuppressive chemotherapy regimens. Primary prophylactic use is indicated when the patient's risk of febrile neutropenia reaches or exceeds 20%, and no equally effective yet safer alternative chemotherapy regimen is available. This activity reviews pegfilgrastim's mechanism of action, dosing guidelines, adverse effect profile, and pertinent drug interactions. A detailed understanding of pegfilgrastim's pharmacological properties enables clinicians to tailor treatments more precisely, ensuring safe and effective care tailored to individual patient needs. The information includes evidence-based strategies to minimize adverse effects and enhance therapeutic outcomes associated with pegfilgrastim administration. Additionally, the activity highlights the importance of interprofessional collaboration in optimizing patient outcomes. Knowledge gained from participation supports informed clinical decision-making, leading to improved patient management and clinical results during pegfilgrastim therapy.

Objectives:

• Evaluate the mechanism of action of pegfilgrastim.
• Identify the indications for pegfilgrastim administration.
• Assess the adverse event profile of pegfilgrastim.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from pegfilgrastim therapy.

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Indications

Pegfilgrastim is a pegylated granulocyte colony-stimulating factor that is FDA-approved to decrease the risk of patients developing febrile neutropenia while receiving myelosuppressive chemotherapy.[1][2] For primary prophylaxis, the risk of developing febrile neutropenia should be 20% or higher, and there should be no other safer regimen that is equally effective available to the patient. Definable risk factors, as listed here, determine a patient's chance of developing febrile neutropenia:

• Aged 65 or older
• Advanced disease
• Previous chemotherapy or radiation therapy
• Preexisting neutropenia or bone marrow involvement with a tumor
• Infection
• Open wounds or having undergone recent surgery
• Poor performance or nutritional status
• Impaired renal function
• Inadequate liver function
• Cardiovascular disease
• Multiple comorbid conditions
• HIV

The risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens. Therefore, individualized, patient-based decisions are essential when deciding whether a granulocyte-colony-stimulating factor is required.[3] The indications are summarized below.

FDA-Approved Indications

• Pegfilgrastim reduces the risk of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.[4] According to the American Society of Clinical Oncology (ASCO) guidelines, pegfilgrastim can be administered to prevent febrile neutropenia.[5]

• Pegfilgrastim is also FDA-approved to help increase the survival of patients exposed to myelosuppressive doses of radiation. Receiving acute myelosuppressive doses of radiation leads to a condition known as acute radiation syndrome, and pegfilgrastim is indicated for patients with this condition.[6]

Off-Label Uses

• Pegfilgrastim may be administered to patients who are undergoing autologous transplantation. However, it should only be done under expert supervision.[7] According to the American Society for Blood and Marrow Transplantation, pegfilgrastim can be used with leukapheresis for chemotherapy plus growth factor mobilization.[8]

Mechanism of Action

Pegfilgrastim is the long-acting form of filgrastim, a granulocyte colony-stimulating factor. Pegfilgrastim has a polyethylene glycol molecule covalently bound to it, resulting in prolonged action duration. This medication helps prevent febrile neutropenia by increasing the body's neutrophil level and inducing neutrophil proliferation, differentiation, and maturation. Pegfilgrastim also enhances the survival of mature neutrophils.[9]

Pharmacokinetics

Absorption: Subcutaneous pegfilgrastim has a lower absolute bioavailability compared to filgrastim. The drug's absorption is primarily mediated through the lymphatic system due to the PEG group attached to the molecule, which increases its size. As a result, pegfilgrastim is slowly absorbed, with peak concentrations typically occurring 1 to 2 days after subcutaneous administration.

Distribution: The volume of distribution is approximately 170 L.

Metabolism: Pegfilgrastim is internalized by the neutrophil and subsequently undergoes nonspecific degradation.

Excretion: Pegfilgrastim's serum clearance is 14 mL/h/kg. Pegfilgrastim is formed by conjugating a polyethylene glycol (PEG) moiety to filgrastim, resulting in a larger molecule. This modification reduces renal clearance via glomerular filtration, making neutrophil-mediated clearance the primary elimination route. The dosage and the absolute neutrophil count influence the clearance of pegfilgrastim. In patients with neutropenia, the drug's biological activity is prolonged due to the reduced availability of mature neutrophils to clear it from circulation.[10]

Administration

Available Dosage Forms and Strengths

Pegfilgrastim has specific administration instructions for both the prevention of febrile neutropenia and the hematopoietic sub-syndrome known as acute radiation syndrome. 

Pegfilgrastim has 2 administration options: one is a prefilled syringe, and the other is an on-body injector.[11] The pegfilgrastim prefilled syringe and on-body injector are typically given on the back of the upper arm or the abdomen, at least 2 inches from the navel. When receiving pegfilgrastim in the prefilled syringe, the patient must make an extra trip to a healthcare facility for subcutaneous administration by a healthcare professional. With the on-body injector, the patient can have it administered the day of their chemotherapy regimen before leaving the clinic, improving patient satisfaction and compliance.

The healthcare professional fills the on-body injector with the pegfilgrastim dose immediately before applying it to the patient's skin. Once filled with the medication, the unit activates automatically. The on-body injector deploys a needle 3 minutes after activation, which the healthcare provider inserts into the patient subcutaneously. The device is then attached to the patient via its adhesive backing. The pegfilgrastim dose is not injected into the patient until 27 hours after activation. Following administration, the patient may appropriately discard the on-body injector.[12] 

Adult Dosage

Myelosuppressive chemotherapy: To prevent febrile neutropenia, a 6 mg pegfilgrastim dose is given to the patient at least 24 hours after receiving chemotherapy.[3] The patient should also receive pegfilgrastim with the first dose of chemotherapy, and administrations should continue throughout their subsequent chemotherapy cycles. Pegfilgrastim should not be given to children under 45 kg because they require weight-based dosing. Since the prefilled syringe and on-body injector both administer precisely 6 mg of pegfilgrastim and have no marks for measuring, they should not be used for patients who require weight-based dosing.[3]

Acute radiation syndrome: To prevent acute radiation syndrome, the recommended dose of pegfilgrastim is 2 doses of 6 mg each, and they should be administered 1 week apart after the patient has undergone radiation exposure therapy.[6] 

Specific Patient Populations

Hepatic impairment: No dosage adjustments are specified in the product labeling; research is required.

Renal impairment: No dosage adjustment is necessary in cases of renal impairment.[9] Pegfilgrastim may cause glomerulonephritis with acute kidney injury. Milder cases might be overlooked; routine renal function and urinalysis are essential.[13]

Pregnancy considerations: There is limited data on the use of pegfilgrastim in pregnant women to assess the risk of congenital disabilities, miscarriage, or adverse outcomes for the mother or fetus. However, filgrastim use during pregnancy has not been linked to significant congenital disabilities, miscarriage, or adverse maternal or fetal effects. International consensus suggests that using granulocyte growth factors is likely safe, although data remain limited.[14]

Breastfeeding considerations: Filgrastim, a recombinant G-CSF, and pegfilgrastim are minimally excreted into breast milk, with levels becoming undetectable within 3 days after injection. Withholding breastfeeding for up to 3 days post-injection is an option. However, the effects of filgrastim or pegfilgrastim on lactation and infant health have not been fully established. Caution and counseling of the mother regarding risk and benefit are recommended due to the limited data.[15]

Pediatric patients: The dose of pegfilgrastim for pediatric patients is based on weight. Caution and close monitoring are advised. The subcutaneous doses for children based on weight ranges are listed below.

• <10 kg: 0.1 mg/kg
• 10 to 20 kg: 1.5 mg
• 21 to 30 kg: 2.5 mg
• 31 to 44 kg: 4 mg
• ≥45 kg: 6 mg

Older patients: No differences in safety and efficacy have been observed compared to younger patients. Studies show that pegfilgrastim reduces hospitalizations from neutropenia by approximately 50%.[16]

Adverse Effects

The most common adverse effect experienced with pegfilgrastim is bone pain. Bone pain associated with pegfilgrastim may be managed with analgesics, such as acetaminophen or NSAIDs, which remain first-line options per ASCO guidelines.[17] NSAIDs may not be an appropriate option for pain relief in some patient populations, such as older adults or those with kidney disease. Although some studies, including the NOLAN phase 2 trial, have explored the use of loratadine for preventing bone pain, it is not recommended by ASCO.[18]

Drug-Drug Interactions

• Clozapine: Clozapine has the potential to induce neutropenia and agranulocytosis, whereas granulocyte colony-stimulating factor (G-CSF) promotes the production of neutrophils. When administered concurrently, G-CSF may mitigate the neutropenic effects associated with clozapine, necessitating careful monitoring.[19] When pegfilgrastim is used with drugs that cause neutropenia, the absolute neutrophil count should be monitored.[20]

• Exagamglogene: Granulocyte colony-stimulating factor should be used cautiously after day 21 to aid neutrophil recovery following myeloablative conditioning. This promotes safe immune system reconstitution to maintain the efficacy of exagamglogene in sickle cell disease.[21]

Contraindications

Pegfilgrastim can cause hypersensitivity reactions.[22] Therefore, it is contraindicated for patients with a history of sensitivity to pegfilgrastim, filgrastim, or any formulation component. The additional warnings and precautions as per labeling are given below.

Warnings and Precautions

• Splenic rupture: Left upper quadrant or shoulder pain with splenomegaly may be observed. Splenic rupture may occur following pegfilgrastim administration.[23][24]

• Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving pegfilgrastim. ARDS should be considered if patients exhibit fever, lung infiltrates, or respiratory distress after pegfilgrastim administration. Discontinue pegfilgrastim if ARDS is confirmed. Rare cases of interstitial pneumonia have been reported.[25]

• Severe allergic reactions: The first dose of pegfilgrastim can cause severe allergic reactions, including anaphylaxis. Discontinue pegfilgrastim permanently in patients who experience severe allergic reactions and avoid its use in patients with a history of severe allergic reactions to pegfilgrastim or filgrastim. 

• Sickle cell disorders: Pegfilgrastim can induce severe, potentially fatal sickle cell crises in patients with sickle cell disease. Discontinue pegfilgrastim if a sickle cell crisis occurs.[26]

• Glomerulonephritis: Some patients receiving pegfilgrastim may develop glomerulonephritis, with signs like azotemia, hematuria, and proteinuria. Consider stopping the pegfilgrastim in glomerulonephritis.

• Thrombocytopenia: Thrombocytopenia can occur; clinicians must monitor platelet counts.

• Capillary leak syndrome: Systemic capillary leak syndrome (SCLS) is caused by increased capillary permeability to proteins. Fluid extravasation from the blood vessels leads to hypotension, pleural effusion, anasarca, and pericardial effusion. Severe cases of SCLS may cause multiorgan dysfunction, cardiovascular collapse, shock, and death. Close monitoring and appropriate treatment, including possible intensive care, are essential.[27][28]

• Aortitis: Aortitis can occur during the initial phase of pegfilgrastim therapy. Discontinue pegfilgrastim if aortitis is suspected.[29][30][31]

• Myelodysplastic syndrome and acute myeloid leukemia: Pegfilgrastim with chemotherapy/radiotherapy increases the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinicians must monitor these patients for MDS or AML.[32][33]

Monitoring

Since pegfilgrastim works on neutrophils to prevent febrile neutropenia, it is imperative to monitor the patient's complete blood count throughout the treatment regimen, with particular attention given to the white blood cell count.[17] Pegfilgrastim has been shown to cause leukocytosis, so it is essential to monitor for elevated white blood cell counts exceeding 11,000/mm³.[34] Pegfilgrastim and all other granulocyte colony-stimulating factors can also cause capillary leak syndrome. Therefore, it is vital to monitor for signs of capillary leak syndrome, which include hypotension, edema, and hypoalbuminemia.[35] Monitoring the patient's temperature to detect the potential onset of febrile neutropenia is also critical.[17]

Toxicity

Signs and Symptoms of Overdose

The maximum safe dose of pegfilgrastim has not been established. The highest dose studied in clinical trials is 300 μg/kg. There have been instances of accidental overdoses occurring in patients. In one case, the patient was a 79-year-old man who self-administered pegfilgrastim for 8 days in a row. He experienced no symptoms during this time but was monitored closely by his doctor 3 times a week, during which he only complained of bone pain. In another case, the patient was a 69-year-old man who self-administered a 36 mg overdose of pegfilgrastim. He was admitted to the hospital, where clinical staff observed leukocytosis, bone pain, and rhinorrhea. Due to the current lack of appropriate treatment for pegfilgrastim overdose, the best course of action for overdose is prevention by vigilant monitoring for signs and symptoms of toxicity.[36]

Management of Overdose

There is no antidote for pegfilgrastim.[37] Emergency medicine physicians should provide supportive care. Consult a medical toxicologist or the National Poison Control Center for complicated cases or pediatric patients.[38]

Enhancing Healthcare Team Outcomes

Cancer is a complex disease state requiring interprofessional communication between many healthcare professionals. The administration of pegfilgrastim to patients with cancer who are receiving myelosuppressive chemotherapy is only a small part of the patient's entire treatment regimen. However, exceptional patient-centered care is still required when given to the patient. Some examples of the roles of each interprofessional healthcare team member are:

• Clinicians must monitor the patient carefully for any signs of adverse events, especially in the case of accidental overdose.[36]
• Clinicians must also appropriately administer pegfilgrastim if given in the pre-filled syringe. They must also attach the on-body injector properly when using this option.[12]
• Pharmacists must help ensure that the patient is receiving the correct dose of pegfilgrastim to prevent an accidental overdose as well as the adverse effects associated with an overdose. Pharmacists must also help educate patients on why they are receiving pegfilgrastim.[36]

Each healthcare team member plays a vital role in the patient's overall well-being while being treated for cancer. An interprofessional team approach with open communication among physicians, advanced practice providers, oncologists, pharmacists, and nurses can reduce adverse effects and improve outcomes associated with pegfilgrastim therapy.

Review Questions

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Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Nafisa King declares no relevant financial relationships with ineligible companies.

Disclosure: Tibb Jacobs declares no relevant financial relationships with ineligible companies.