Filgrastim

Filgrastim is a recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) made in Escherichia coli. Natural G-CSF is the glycoprotein that regulates the production and release of functional neutrophils from the bone marrow, and filgrastim reproduces this action for a short time after each dose. The filgrastim products authorised centrally by the European Medicines Agency are biosimilar medicinal products; the originator, Neupogen, is authorised nationally.

Mechanism of Action

• Receptor binding: filgrastim binds specific G-CSF receptors on haematopoietic cells and stimulates the proliferation, differentiation and maturation of neutrophil progenitors. It also helps release neutrophils from the bone marrow into the blood.
• Neutrophil response: circulating neutrophil counts rise markedly within 24 hours, with a minor rise in monocytes, and the increase is dose-dependent at recommended doses. The neutrophils formed show normal or enhanced chemotactic and phagocytic function. In some patients with severe chronic neutropenia, eosinophils and basophils also rise slightly.
• After the last dose: circulating neutrophil counts fall by 50% within 1–2 days and return to normal levels within 1–7 days.
• Effect during chemotherapy: filgrastim significantly reduces the incidence, severity and duration of neutropenia and febrile neutropenia. After induction chemotherapy for acute myeloid leukaemia, or myeloablative therapy followed by bone marrow transplantation, it shortens febrile neutropenia, antibiotic use and hospital stay. It did not reduce the incidence of fever or documented infections in either setting, nor the duration of fever after myeloablative therapy and transplantation.
• Stem cell mobilisation: alone or after chemotherapy, filgrastim moves haematopoietic progenitor cells into the peripheral blood, where they can be collected. Recipients of allogeneic cells mobilised this way regained platelet counts without support sooner than recipients of allogeneic bone marrow.

Pharmacokinetics

• Absorption: after a single subcutaneous dose of 0.5 MU/kg (5 mcg/kg) the peak serum concentration is reached after about 4.5 hours (mean 4.5 ± 0.9 hours). Absolute bioavailability after subcutaneous injection is about 60–70%.
• Distribution: the volume of distribution in blood is about 150 mL/kg. After subcutaneous injection of recommended doses, serum concentrations stay above 10 ng/mL for 8–16 hours. Serum concentration rises linearly with dose, whether given intravenously or subcutaneously. Information on plasma protein binding is limited.
• Metabolism: like other G-CSFs, filgrastim is cleared mainly by neutrophils, which take it up through G-CSF receptors and degrade it. Neutrophil elastase also breaks it down outside cells.
• Elimination: after single subcutaneous doses the median serum half-life ranged from 2.7 hours (1.0 MU/kg) to 5.7 hours (0.25 MU/kg), and lengthened to about 8.5–14 hours after 7 days of dosing. Clearance after intravenous dosing is about 0.5–0.7 mL/min/kg. Continuous infusion for up to 28 days in patients recovering from autologous bone marrow transplantation showed no accumulation and similar half-lives.
• Special populations: in severe renal or hepatic impairment the pharmacokinetic and pharmacodynamic profile is similar to that of normal individuals, so no dose adjustment is needed. No special studies were done in elderly patients. Safety and efficacy in children receiving chemotherapy are similar to adults; 65% of the patients in the severe chronic neutropenia programme were under 18.
• Biosimilar comparison: crossover studies in 204 healthy volunteers showed that the pharmacokinetic profile of the biosimilar studied was comparable to that of its reference product after subcutaneous and intravenous administration.

The filgrastim biosimilars whose SmPCs were reviewed share the same five indications.

• Chemotherapy-induced neutropenia: reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). Safety and efficacy are similar in adults and children receiving cytotoxic chemotherapy.
• Myeloablative therapy followed by bone marrow transplantation: reduction in the duration of neutropenia in patients considered to be at increased risk of prolonged severe neutropenia.
• Mobilisation of peripheral blood progenitor cells (PBPCs).
• Severe chronic neutropenia (SCN): in children or adults with severe congenital, cyclic or idiopathic neutropenia, an absolute neutrophil count (ANC) of 0.5 × 10⁹/L or lower and a history of severe or recurrent infections, long-term administration to increase neutrophil counts and reduce the incidence and duration of infection-related events.
• Advanced HIV infection: treatment of persistent neutropenia (ANC 1.0 × 10⁹/L or lower) to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.

• Hypersensitivity to filgrastim or to any of the excipients.

The most serious reactions are anaphylaxis, serious lung reactions (including interstitial pneumonia and acute respiratory distress syndrome), capillary leak syndrome, severe splenomegaly or splenic rupture, transformation to myelodysplastic syndrome or leukaemia in patients with severe chronic neutropenia, graft-versus-host disease after allogeneic bone marrow or peripheral blood progenitor cell transplantation, and sickle cell crisis in sickle cell disease. The most commonly reported reactions are pyrexia, musculoskeletal pain (bone pain, back pain, arthralgia, myalgia, pain in an extremity, musculoskeletal chest pain, neck pain), anaemia, vomiting and nausea. In cancer trials, musculoskeletal pain was mild or moderate in 10% of patients and severe in 3%.

Very common (≥1/10): thrombocytopenia, anaemia, headache, diarrhoea, vomiting, nausea, alopecia, musculoskeletal pain, fatigue, mucosal inflammation, pyrexia.

Common (≥1/100 to <1/10): sepsis, bronchitis, upper respiratory tract infection, urinary tract infection, splenomegaly, decreased haemoglobin, decreased appetite, raised blood lactate dehydrogenase, insomnia, dizziness, hypoaesthesia, paraesthesia, hypertension, hypotension, haemoptysis, dyspnoea, cough, oropharyngeal pain, epistaxis, oral pain, constipation, hepatomegaly, raised alkaline phosphatase, rash, erythema, muscle spasms, dysuria, haematuria, chest pain, pain, asthenia, malaise, peripheral oedema, transfusion reaction.

Uncommon (≥1/1,000 to <1/100): leukocytosis, hypersensitivity, drug hypersensitivity, graft-versus-host disease, hyperuricaemia, raised blood uric acid, veno-occlusive disease, acute respiratory distress syndrome, respiratory failure, pulmonary oedema, pulmonary haemorrhage, interstitial lung disease, lung infiltration, hypoxia, raised AST, raised gamma-glutamyl transferase, maculopapular rash, osteoporosis, proteinuria, injection site reaction.

Rare (≥1/10,000 to <1/1,000): splenic rupture, sickle cell crisis in sickle cell anaemia, extramedullary haematopoiesis, anaphylactic reaction, decreased blood glucose, pseudogout (chondrocalcinosis pyrophosphate), fluid volume disturbances, capillary leak syndrome, aortitis, cutaneous vasculitis, Sweet’s syndrome (acute febrile neutrophilic dermatosis), decreased bone density, exacerbation of rheumatoid arthritis, glomerulonephritis, abnormal urine findings.

• Cytotoxic chemotherapy: the safety and efficacy of filgrastim given on the same day as myelosuppressive chemotherapy have not been firmly established. Because rapidly dividing myeloid cells are sensitive to chemotherapy, filgrastim is not recommended from 24 hours before to 24 hours after a chemotherapy dose.
• 5-fluorouracil: preliminary evidence from a small number of patients given filgrastim together with 5-fluorouracil suggests that the severity of neutropenia may be worse.
• Other haematopoietic growth factors and cytokines: possible interactions have not yet been investigated in clinical trials.
• Lithium: lithium promotes the release of neutrophils and is likely to strengthen the effect of filgrastim. The interaction has not been formally investigated, but there is no evidence that it is harmful.

Filgrastim should be given only in collaboration with an oncology centre experienced in G-CSF treatment and in haematology, with the necessary diagnostic facilities. Mobilisation and apheresis procedures are performed with an oncology-haematology centre that has acceptable experience and can monitor haematopoietic progenitor cells correctly. Doses are given per kilogram of body weight, in million units (MU) and micrograms (mcg). The name and batch number of the product given are recorded.

Established Cytotoxic Chemotherapy

• Dose: 0.5 MU/kg/day (5 mcg/kg/day). The first dose is given at least 24 hours after cytotoxic chemotherapy. In randomised trials a subcutaneous dose of 230 mcg/m²/day (4.0 to 8.4 mcg/kg/day) was used.
• Duration: daily until the expected neutrophil nadir has passed and the count has returned to the normal range. After chemotherapy for solid tumours, lymphomas and lymphoid leukaemia this is expected to take up to 14 days; after induction and consolidation for acute myeloid leukaemia it may take substantially longer (up to 38 days), depending on the chemotherapy.
• Do not stop early: neutrophil counts typically rise transiently 1–2 days after starting, but treatment should not stop before the expected nadir has passed and the count has recovered. Premature discontinuation is not recommended.
• Route: a daily subcutaneous injection, preferred in most cases, or a daily intravenous infusion over 30 minutes diluted in 5% glucose solution. A single-dose study suggested that intravenous dosing may shorten the duration of effect; the relevance to repeated dosing is unclear.

Myeloablative Therapy Followed by Bone Marrow Transplantation

• Starting dose: 1.0 MU/kg/day (10 mcg/kg/day), the first dose at least 24 hours after chemotherapy and at least 24 hours after the bone marrow infusion.
• Titration after the nadir: when the ANC stays above 1.0 × 10⁹/L for 3 consecutive days, reduce to 0.5 MU/kg/day (5 mcg/kg/day); if it then stays above 1.0 × 10⁹/L for 3 more days, stop. If the ANC falls below 1.0 × 10⁹/L during treatment, the dose is raised again following the same steps.
• Route: a 30-minute or 24-hour intravenous infusion, or a continuous 24-hour subcutaneous infusion, diluted in 20 mL of 5% glucose solution.

Mobilisation of Peripheral Blood Progenitor Cells

• Autologous transplantation, filgrastim alone: 1.0 MU/kg/day (10 mcg/kg/day) for 5–7 consecutive days. One or two leukaphereses on days 5 and 6 are often sufficient; more may be needed. Dosing continues until the last leukapheresis. It is given as a 24-hour continuous subcutaneous infusion (diluted in 20 mL of 5% glucose solution) or a subcutaneous injection.
• Autologous transplantation, after myelosuppressive chemotherapy: 0.5 MU/kg/day (5 mcg/kg/day) by subcutaneous injection from the first day after chemotherapy until the expected nadir has passed and the count is back in the normal range. Leukapheresis is timed for when the ANC rises from below 0.5 × 10⁹/L to above 5.0 × 10⁹/L; one leukapheresis is often enough after limited chemotherapy, and more are recommended otherwise.
• Healthy donors before allogeneic transplantation: 1.0 MU/kg/day (10 mcg/kg/day) by subcutaneous injection for 4–5 consecutive days. Leukapheresis starts on day 5 and continues to day 6 if needed to collect 4 × 10⁶ CD34+ cells/kg of the recipient’s body weight.

Severe Chronic Neutropenia

• Starting dose: congenital neutropenia 1.2 MU/kg/day (12 mcg/kg/day); idiopathic or cyclic neutropenia 0.5 MU/kg/day (5 mcg/kg/day), as a single dose or in divided doses, by daily subcutaneous injection.
• Adjustment: daily until the neutrophil count has reached and can be kept above 1.5 × 10⁹/L, then the minimal effective dose to maintain it is established. After 1–2 weeks the dose may be doubled or halved depending on response, and then adjusted every 1–2 weeks to keep the average neutrophil count between 1.5 and 10 × 10⁹/L. Faster escalation may be considered in severe infection. Long-term daily administration is needed.
• Upper doses: 97% of responders had a complete response at 24 mcg/kg/day or less; long-term safety above 24 mcg/kg/day has not been established.

HIV Infection

• Reversal of neutropenia: starting dose 0.1 MU/kg/day (1 mcg/kg/day), titrated up to a maximum of 0.4 MU/kg/day (4 mcg/kg/day) until a normal neutrophil count is reached and maintained (ANC above 2.0 × 10⁹/L). More than 90% of patients responded, with reversal in a median of 2 days; fewer than 10% needed up to 1.0 MU/kg/day (10 mcg/kg/day).
• Maintenance: once neutropenia has reversed, the minimal effective dose is established, starting with alternate-day dosing of 30 MU/day (300 mcg/day) and adjusting to keep the ANC above 2.0 × 10⁹/L. In studies 30 MU/day was needed on 1–7 days a week (median 3 days). Long-term administration may be needed. Given by subcutaneous injection.

Special Populations

• Elderly: few elderly patients were in clinical trials and no special studies were done, so no specific dosing recommendation can be made.
• Renal or hepatic impairment: no dose adjustment, as the pharmacokinetic and pharmacodynamic profile is similar to that in normal individuals.
• Children: dosing in children receiving myelosuppressive chemotherapy is the same as in adults. In severe chronic neutropenia, 65% of trial patients were under 18 years, efficacy was clear, and the safety profile was no different.
• Pre-filled syringe: syringes with a spring-type needle guard, as in at least one product reviewed, are not designed to measure volumes below 0.3 mL, so doses below 0.3 mL should not be given with them. The solution may be diluted if required, as set out in the SmPC of the product used.

Traceability

To improve the traceability of granulocyte colony-stimulating factors, the name and batch number of the product given should be clearly recorded.

Hypersensitivity

Hypersensitivity, including anaphylactic reactions, can occur at the first or a later treatment. Filgrastim is stopped permanently in patients with clinically significant hypersensitivity, and is not given to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.

Lung Reactions

Interstitial lung disease and other pulmonary reactions have been reported after G-CSF. Patients with a recent history of lung infiltrates or pneumonia may be at higher risk. Cough, fever and dyspnoea together with radiological infiltrates and worsening lung function can be early signs of acute respiratory distress syndrome; filgrastim should then be stopped and appropriate treatment given.

Glomerulonephritis

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

Capillary Leak Syndrome

Capillary leak syndrome, characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration, can be life-threatening if treatment is delayed. Patients who develop symptoms need close monitoring and standard symptomatic treatment, which may include intensive care.

Spleen

Splenomegaly, usually without symptoms, and splenic rupture, some fatal, have been reported in patients and in healthy donors. Spleen size should be monitored (for example by examination or ultrasound), and splenic rupture should be considered in anyone with left upper abdominal pain or shoulder-tip pain. In severe chronic neutropenia, dose reductions slowed or stopped splenic enlargement, and 3% of patients needed a splenectomy.

White Cell and Platelet Counts

• Leukocytosis: white blood cell counts of 100 × 10⁹/L or more were seen in under 5% of cancer patients given more than 0.3 MU/kg/day, without directly attributable harm. Counts are checked at regular intervals; filgrastim is stopped immediately if leukocytes exceed 50 × 10⁹/L after the expected nadir, and stopped or reduced during PBPC mobilisation if they exceed 70 × 10⁹/L.
• Thrombocytopenia: platelet counts are monitored closely, especially in the first weeks. In severe chronic neutropenia, temporary discontinuation or a dose reduction is considered if platelets fall below 100 × 10⁹/L.
• Immunogenicity: as with all therapeutic proteins, antibodies can form. Rates are generally low, and binding antibodies have not so far been linked to neutralising activity.

Underlying Blood and Bone Conditions

• Myelodysplastic syndrome and chronic myeloid leukaemia: safety and efficacy have not been established, and filgrastim is not indicated for them. Particular care is needed to tell blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
• Acute myeloid leukaemia: use with caution in secondary disease; safety and efficacy in de novo disease under 55 years of age with good cytogenetics have not been established.
• Malignant cell growth: G-CSF can promote the growth of myeloid cells in vitro, and similar effects may occur on some non-myeloid cells in vitro.
• Sickle cell trait or disease: sickle cell crises, some fatal, have been reported, so doctors should be cautious.
• Osteoporosis: bone density monitoring may be indicated in patients with underlying osteoporotic bone disease on continuous treatment for more than 6 months.

Cancer Patients Receiving Chemotherapy

• Filgrastim should not be used to raise the dose of cytotoxic chemotherapy beyond established regimens. Intensified doses may increase toxicity, including cardiac, pulmonary, neurological and skin effects, without a shown tumour benefit.
• Filgrastim alone does not prevent thrombocytopenia and anaemia caused by chemotherapy, and full-dose schedules may increase that risk. Platelet counts and haematocrit are checked regularly.
• In a post-marketing study, myelodysplastic syndrome and acute myeloid leukaemia were associated with pegfilgrastim plus chemotherapy or radiotherapy in patients with breast or lung cancer. A similar association was not seen with filgrastim, but these patients should be watched for signs.
• The neutrophil response may be weaker in patients with substantially reduced myeloid progenitors, for example after extensive radiotherapy or chemotherapy or with bone marrow infiltration by tumour.
• Veno-occlusive disease and fluid volume disturbances have been reported occasionally after high-dose chemotherapy with transplantation. Graft-versus-host disease, with fatalities, has been reported with G-CSF after allogeneic bone marrow transplantation.
• Increased bone marrow activity can cause transient abnormal bone scans, which should be considered when reading bone images.
• Aortitis has been reported after G-CSF in healthy subjects and cancer patients, with fever, abdominal pain, malaise, back pain and raised inflammatory markers. It was mostly diagnosed by CT scan and generally resolved after G-CSF was withdrawn.

Stem Cell Mobilisation

• No randomised comparison of the two mobilisation methods (filgrastim alone or with chemotherapy) exists in the same population, so the choice depends on the overall treatment aims.
• Very extensive earlier myelosuppressive therapy can leave mobilisation below the recommended minimum yield of 2.0 × 10⁶ CD34+ cells/kg. Melphalan, carmustine and carboplatin given over long periods can reduce yield, although they can be combined with filgrastim effectively. Mobilisation is best planned early in the course, and if yields are inadequate, treatment not needing progenitor support should be considered.
• Healthy donors: mobilisation brings the donor no direct clinical benefit and should be considered only for allogeneic stem cell transplantation, in donors who meet the usual clinical and laboratory criteria. Safety and efficacy were not assessed in donors under 16 or over 60 years. Transient thrombocytopenia (platelets below 100 × 10⁹/L) occurred in 35% of donors studied after filgrastim and leukapheresis. If more than one leukapheresis is needed, donors with platelets below 100 × 10⁹/L beforehand need particular attention.
• Recipients of allogeneic PBPCs: current data suggest an increased risk of acute and chronic graft-versus-host disease compared with bone marrow transplantation.

Severe Chronic Neutropenia

• Filgrastim is not given to patients with severe congenital neutropenia who develop leukaemia or show signs of leukaemic evolution.
• Before treatment, complete blood counts with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype, help distinguish severe chronic neutropenia from aplastic anaemia, myelodysplasia and myeloid leukaemia. Causes of transient neutropenia, such as viral infections, are excluded.
• Myelodysplastic syndrome or leukaemia occurred in about 3% of trial patients, only in congenital neutropenia, and its link to filgrastim is uncertain. About 12% of patients with normal cytogenetics at baseline later showed abnormalities, including monosomy 7. Bone marrow morphology and cytogenetics are examined about every 12 months.
• Anaemia and transient rises in myeloid progenitors can occur and need close monitoring of cell counts. Haematuria was common and proteinuria occurred in a few patients, so urinalysis is done regularly.
• Safety and efficacy in neonates and in autoimmune neutropenia have not been established.

HIV Infection

• The ANC is monitored closely, daily for the first 2–3 days, at least twice weekly for the first 2 weeks, and then weekly or every other week during maintenance. With intermittent 30 MU/day dosing the ANC can fluctuate widely, so blood is taken just before a scheduled dose to find the trough.
• Filgrastim alone does not prevent thrombocytopenia and anaemia caused by myelosuppressive treatment, so blood counts are monitored regularly.
• Neutropenia can be due to bone marrow-infiltrating infections such as Mycobacterium avium complex or to malignancies such as lymphoma; the underlying condition should be treated as well. The effect of filgrastim in these cases is not well established.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no or few data in pregnant women. Animal studies showed reproductive toxicity, with embryo loss in rabbits at high multiples of clinical exposure in the presence of maternal toxicity, and transplacental passage in pregnant women has been reported in the literature. Filgrastim is not recommended during pregnancy.
• Breastfeeding: it is unknown whether filgrastim or its metabolites pass 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 filgrastim, weighing the benefit of breastfeeding to the child against the benefit of therapy to the woman.
• Fertility: filgrastim did not affect reproductive performance or fertility in male or female rats.

Sorbitol and Sodium

The syringes contain sorbitol (E420), 50 mg per mL. Patients with hereditary fructose intolerance must not be given the medicine unless strictly necessary. Babies and young children under 2 years may not yet be diagnosed with this intolerance, and intravenous medicines containing sorbitol or fructose may be life-threatening for them, so they should not receive them unless there is an overwhelming clinical need and no alternative. A detailed history of fructose-intolerance symptoms is taken before use. The medicine contains less than 1 mmol (23 mg) sodium per dose, so it is essentially sodium-free. Excipients differ slightly between brands, so the SmPC of the product used applies.

Effect on Driving

Filgrastim may have a minor influence on the ability to drive and use machines. Dizziness may occur after administration.

Store pre-filled syringes in a refrigerator at 2–8 °C, in the outer carton to protect them from light, and keep the cold chain during transport and delivery. Zefylti must not be frozen, whereas for Tevagrastim accidental exposure to freezing temperatures does not affect stability.

For ambulatory use, one single period out of the refrigerator at room temperature (not above 25 °C) is allowed within the shelf life. The length depends on the product: 72 hours for Zefylti (the syringe is then discarded and not put back in the refrigerator), up to 4 days for Tevagrastim (it may go back to the refrigerator if unused, but syringes kept above 8 °C for more than 4 days are discarded), and 8 days for one other biosimilar (then discarded). Check the SmPC of the product in use.

After dilution for infusion, chemical and physical stability has been shown for 24 hours at 2–8 °C. For microbiological reasons it should be used immediately; if not, the user is responsible for storage times, which would normally not exceed 24 hours at 2–8 °C unless the dilution was made under controlled and validated aseptic conditions.

3 years for Zefylti and for the other biosimilar whose product information was reviewed; 30 months for Tevagrastim. Other brands may differ, and the expiry date on the carton applies. After dilution for infusion: 24 hours at 2–8 °C, as above.

Prescription only (Rx). The reference SmPC classifies filgrastim as subject to restricted medical prescription, and therapy is given in collaboration with an oncology centre experienced in G-CSF treatment and haematology. Pre-filled syringes are supplied on prescription to the hospital, clinic or oncology centre that administers them or, where the treating team arranges injection at home, to the patient, with cold-chain delivery at 2–8 °C.