Pegfilgrastim

Human granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant methionyl human G-CSF, made in Escherichia coli, with a single 20 kDa polyethylene glycol (PEG) molecule. The PEG chain lowers renal clearance, so the effect lasts long enough for one injection per chemotherapy cycle, where filgrastim needs daily injections. The SmPC notes that the potency of pegfilgrastim should not be compared with that of any other pegylated or non-pegylated protein of the same therapeutic class. The biosimilar pegfilgrastim products listed on this page were authorised on the basis of comparability with Neulasta.

Mechanism of Action

• Receptor binding: pegfilgrastim binds the same G-CSF receptor as natural G-CSF, on granulocytic precursors and mature neutrophils. Binding changes the shape of the receptor and activates several signalling pathways (JAK/STAT, PI3K/AKT and MAPK/ERK), which increase the proliferation and differentiation of granulocyte progenitor cells, drive their maturation, and improve the survival and function of mature neutrophils.
• Same mode of action as filgrastim: peripheral neutrophil counts rise markedly within 24 hours, with minor increases in monocytes and/or lymphocytes. The neutrophils produced show normal or enhanced function in tests of chemotaxis and phagocytosis.
• Self-regulating clearance: neutrophils themselves clear pegfilgrastim. Serum concentrations are therefore sustained during chemotherapy-induced neutropenia and fall quickly once neutrophils begin to recover.
• Clinical effect: in two randomised, double-blind pivotal studies in high-risk stage II–IV breast cancer given doxorubicin and docetaxel, one dose per cycle reduced the duration of neutropenia and the incidence of febrile neutropenia similarly to daily filgrastim (a median of 11 daily injections). Without growth factor support, this regimen gives a mean 5 to 7 days of grade 4 neutropenia and a 30–40% incidence of febrile neutropenia. In one study (n = 157) with a fixed 6 mg dose, the mean duration of grade 4 neutropenia was 1.8 days with pegfilgrastim and 1.6 days with filgrastim (difference 0.23 days, 95% CI −0.15 to 0.63).
• Growth of myeloid cells: G-CSF can promote the growth of myeloid cells, including malignant cells, in vitro, and similar effects may be seen on some non-myeloid cells in vitro. It also stimulated human endothelial cells in vitro.

Pharmacokinetics

• Absorption: after a single subcutaneous dose, peak serum concentrations occur 16 to 120 hours after dosing, and concentrations are maintained during the neutropenia that follows myelosuppressive chemotherapy. Absorption depends largely on the lymphatic system.
• Distribution: the volume of distribution is about 170 L (DrugBank). Binding to plasma proteins is considered unlikely.
• Metabolism and elimination: elimination is non-linear. Pegfilgrastim is cleared mainly by neutrophils, which internalise and degrade it after it binds the G-CSF receptor, and this route becomes saturated at higher doses, so clearance falls as the dose rises. Because of the PEG chain, renal filtration plays only a small part. Serum concentration drops rapidly when neutrophils begin to recover. The serum half-life is highly variable, 15 to 80 hours after subcutaneous injection with a median of 42 hours (DrugBank).
• Renal and hepatic impairment: because neutrophils clear the drug, pharmacokinetics are not expected to be affected by renal or hepatic impairment. In an open-label single-dose study (n = 31), various stages of renal impairment, including end-stage renal disease, had no effect on pharmacokinetics.
• Elderly: limited data indicate pharmacokinetics in people over 65 years similar to those in adults.
• Children: in 37 children with sarcoma given 100 µg/kg after chemotherapy, the youngest group (0–5 years) had higher exposure (mean AUC 47.9 ± 22.5 µg·h/mL) than children aged 6–11 years (22.0 ± 13.1) and 12–21 years (29.3 ± 23.2). Apart from the youngest group, mean AUC was similar to that of adults with high-risk stage II–IV breast cancer given 100 µg/kg after doxorubicin and docetaxel.

• Neutropenia in cancer chemotherapy: reduction in the duration of neutropenia and in the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy, with the exception of chronic myeloid leukaemia and myelodysplastic syndromes.

Neutropenia is a low neutrophil count, and febrile neutropenia is fever with a very low neutrophil count. The use sits between oncology and haematology: the indication covers cancer in general, solid or haematological, apart from those two exceptions, and the SmPC advises caution in de novo acute myeloid leukaemia. The biosimilars listed on this page carry the same indication as Neulasta; the SmPC of the individual product applies.

• Hypersensitivity to pegfilgrastim or to any excipient.

The most frequent reactions are bone pain (very common) and musculoskeletal pain (common). Bone pain is generally mild to moderate and short-lived, and standard analgesics control it in most patients.

Very common (≥1/10): headache, nausea (both seen very commonly in patients receiving chemotherapy); bone pain.

Common (≥1/100 to <1/10): thrombocytopenia, leukocytosis; musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, neck pain); injection-site pain; non-cardiac chest pain.

Uncommon (≥1/1,000 to <1/100): myelodysplastic syndrome, acute myeloid leukaemia; sickle cell anaemia with crisis, splenomegaly, splenic rupture; hypersensitivity reactions, anaphylaxis; elevated uric acid; capillary leak syndrome; acute respiratory distress syndrome, pulmonary adverse reactions (interstitial pneumonia, pulmonary oedema, pulmonary infiltrates, pulmonary fibrosis), haemoptysis; Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis; glomerulonephritis; injection-site reactions; elevated lactate dehydrogenase and alkaline phosphatase; transient elevations in liver enzymes (ALT or AST).

Rare (≥1/10,000 to <1/1,000): aortitis; pulmonary haemorrhage; Stevens-Johnson syndrome.

Some uncommon reactions (sickle cell crisis, splenomegaly, splenic rupture, acute respiratory distress syndrome, Sweet’s syndrome, cutaneous vasculitis, glomerulonephritis and injection-site reactions) were identified after marketing and not in randomised controlled trials in adults; their frequency was estimated statistically from 1,576 patients in nine randomised trials.

Important serious reactions:

• Allergic reactions: skin rash, urticaria, angioedema, dyspnoea, erythema, flushing and hypotension, including anaphylaxis, can occur on first or later treatment.
• Capillary leak syndrome: can be life-threatening if treatment is delayed. It has generally occurred in patients with advanced malignancy or sepsis, patients taking several chemotherapy medicines, or those undergoing apheresis.
• Spleen: splenomegaly is generally without symptoms, and splenic rupture, including fatal cases, has been reported.
• Lungs: interstitial pneumonia, pulmonary oedema, infiltrates and fibrosis; in some cases respiratory failure or acute respiratory distress syndrome, which may be fatal.
• Sickle cell crises in patients with sickle cell trait or disease.
• MDS and AML: an epidemiological study found an increased risk of myelodysplastic syndrome and acute myeloid leukaemia after pegfilgrastim with chemotherapy and/or radiotherapy in breast and lung cancer patients.
• Children: experience is limited. Serious reactions were more frequent in children aged 0–5 years (92%) than in those aged 6–11 years (80%) and 12–21 years (67%) and in adults, and bone pain was the most common reaction.

• Cytotoxic chemotherapy: rapidly dividing myeloid cells are sensitive to cytotoxic drugs, so pegfilgrastim must be given at least 24 hours after chemotherapy. In clinical trials it was given safely 14 days before chemotherapy. Concomitant use with any chemotherapy agent has not been evaluated in patients. In animal models, giving pegfilgrastim at the same time as 5-fluorouracil or other antimetabolites increased myelosuppression.
• Chemotherapy with delayed myelosuppression: safety and efficacy have not been evaluated with agents such as nitrosoureas.
• Other haematopoietic growth factors and cytokines: possible interactions have not been investigated specifically in clinical trials.
• Lithium: lithium also promotes the release of neutrophils. This interaction has not been investigated specifically, and there is no evidence that it would be harmful.
• Other medicines: no specific interaction or metabolism studies have been done, but clinical trials have not shown an interaction with any other medicine.

Treatment should be started and supervised by physicians experienced in oncology and/or haematology. Neulasta is injected under the skin (subcutaneously) into the thigh, abdomen or upper arm. Handling instructions are in section 6.6 of the SmPC; the biosimilars have their own instructions for use.

Recommended Dose

• One 6 mg dose (a single pre-filled syringe) for each chemotherapy cycle, given at least 24 hours after the cytotoxic chemotherapy.
• Pegfilgrastim has not been investigated with high-dose chemotherapy and must not be used to raise the dose of cytotoxic chemotherapy above established regimens.

Special Populations

• Renal impairment: no dose change, including in end-stage renal disease.
• Hepatic impairment and elderly patients: the SmPC gives no separate dose recommendation. Pharmacokinetics are not expected to be affected by hepatic impairment, and limited data show similar pharmacokinetics in patients over 65 years.
• Children and adolescents: safety and efficacy have not been established. The available data are described in the SmPC, but no dose can be recommended.

Traceability

To improve the traceability of G-CSFs, the trade name of the product given must be recorded clearly in the patient file. This matters especially where a biosimilar and the reference product are both in use.

Leukaemia and Myeloid Malignancies

• Limited data suggest a comparable effect to filgrastim on recovery from severe neutropenia in de novo acute myeloid leukaemia (AML), but long-term effects have not been established, so use caution in this group.
• The safety and efficacy of pegfilgrastim have not been investigated in myelodysplastic syndrome, chronic myeloid leukaemia or secondary AML, and it should not be used in these patients. Blast transformation of chronic myeloid leukaemia needs to be distinguished carefully from AML.
• The safety and efficacy in de novo AML patients under 55 years with t(15;17) cytogenetics have not been established.
• In breast and lung cancer patients, pegfilgrastim with chemotherapy and/or radiotherapy has been linked to myelodysplastic syndrome and AML in an observational study. These patients should be monitored for signs and symptoms.

Pulmonary Adverse Events

Interstitial pneumonia has been reported after G-CSF, and patients with a recent history of lung infiltrates or pneumonia may be at higher risk. Cough, fever and dyspnoea with radiological lung infiltrates and worsening lung function, together with a rising neutrophil count, may be early signs of acute respiratory distress syndrome. In that situation, pegfilgrastim should be stopped at the physician’s discretion and appropriate treatment given.

Glomerulonephritis

Glomerulonephritis has been reported with filgrastim and pegfilgrastim and generally resolved after dose reduction or withdrawal. Urinalysis monitoring is recommended.

Capillary Leak Syndrome

Capillary leak syndrome is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients with symptoms should be closely monitored and receive standard symptomatic treatment, which may include intensive care.

Splenomegaly and Splenic Rupture

Spleen size should be monitored carefully (for example by clinical examination or ultrasound). Splenic rupture should be considered in patients with left upper abdominal pain or shoulder tip pain.

Blood Counts

• Platelets and haemoglobin: pegfilgrastim does not prevent thrombocytopenia and anaemia, because full-dose myelosuppressive chemotherapy continues on schedule. Platelet count and haematocrit should be monitored regularly, with special care for chemotherapy known to cause severe thrombocytopenia.
• Leukocytosis: white blood cell counts of 100 × 10⁹/L or higher occurred in under 1% of patients. The rise is transient, usually seen 24 to 48 hours after administration, and consistent with the drug’s pharmacodynamic effect; no adverse events were directly attributed to it. White cell counts should be checked at regular intervals, and the medicine stopped immediately if the count exceeds 50 × 10⁹/L after the expected nadir.

Sickle Cell Disorders

Sickle cell crises have been linked to pegfilgrastim in patients with sickle cell trait or sickle cell disease. Physicians should use caution, monitor clinical parameters and laboratory status, and watch for splenic enlargement and vaso-occlusive crisis.

Hypersensitivity and Stevens-Johnson Syndrome

Hypersensitivity, including anaphylactic reactions, has occurred on first or later treatment. Pegfilgrastim must be stopped permanently in patients with clinically significant hypersensitivity, and must not be given to anyone with a history of hypersensitivity to pegfilgrastim or filgrastim. For a serious allergic reaction, appropriate therapy and close follow-up over several days are needed. Stevens-Johnson syndrome, which can be life-threatening or fatal, has rarely been reported; if it develops, pegfilgrastim must never be restarted in that patient.

Aortitis

Aortitis has been reported after G-CSF in healthy subjects and in cancer patients. Symptoms included fever, abdominal pain, malaise, back pain and raised inflammatory markers (such as C-reactive protein and white cell count). It was usually diagnosed by CT scan and generally resolved after the G-CSF was withdrawn.

Immunogenicity

As with all therapeutic proteins, antibodies can form. The rate of antibody formation against pegfilgrastim is generally low. Binding antibodies occur, as with all biological medicines, but have not been linked to neutralising activity so far.

Other Warnings

• Stem cell mobilisation: safety and efficacy for mobilising blood progenitor cells in patients or healthy donors have not been adequately evaluated.
• Latex: the needle cap of the pre-filled syringe contains dry natural rubber (a latex derivative), which may cause allergic reactions.
• Bone imaging: increased bone marrow activity during growth factor therapy has been linked to transient positive bone-imaging findings, which should be considered when reading scans.
• Sorbitol: each syringe contains 30 mg sorbitol. The additive effect of other sorbitol (or fructose) containing products and dietary sorbitol (or fructose) should be taken into account.
• Sodium: less than 1 mmol (23 mg) per 6 mg dose, that is, essentially ‘sodium-free’.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no or limited data in pregnant women, and animal studies showed reproductive toxicity. Pegfilgrastim is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: there is insufficient information on excretion into human milk, and a risk to newborns and infants cannot be excluded. A decision must be made whether to stop breastfeeding or to stop or abstain from pegfilgrastim, weighing the benefit of breastfeeding for the child against the benefit of therapy for the woman.
• Fertility: pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses about 6 to 9 times the recommended human dose (by body surface area).

Effect on Driving

Pegfilgrastim has no or negligible influence on the ability to drive and use machines.

Store in a refrigerator at 2–8 °C. Neulasta may be exposed to room temperature (not above 30 °C) for one single period of up to 72 hours; if it stays at room temperature for longer, it must be discarded. Do not freeze. Accidental exposure to freezing temperatures for a single period of under 24 hours does not harm stability. Keep the pre-filled syringe in the outer carton to protect it from light. As a refrigerated product, it must be transported and held at 2–8 °C. The biosimilars have their own storage statements in their SmPCs.

3 years for Neulasta pre-filled syringes. Do not use after the expiry date on the pack. The biosimilars state their own shelf life in their SmPCs.

Prescription only (Rx), under restricted medical prescription (Annex II B); treatment is started and supervised by a physician experienced in oncology and/or haematology. The pre-filled syringe is a cold-chain product and is supplied to the patient or the treating clinic on prescription, with delivery at 2–8 °C, for use as directed by the treating team.