Filgrastim

Registered South African indications:

• 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) 
  - In patients undergoing myeloablative therapy followed by bone marrow transplantation (for the reduction of neutropenia and its clinical sequelae)
• Severe chronic neutropenia (SCN) 
  - In patients with severe congenital, cyclic, or idiopathic neutropenia with an ANC ≤0,5x10⁹/l
• Mobilisation of peripheral blood progenitor cell (PBPCs)
     - For the mobilisation of autologous PBPCs alone, or following myelosuppressive chemotherapy
  - For the mobilisation of peripheral blood progenitor cells in normal donors (allogeneic) PBPC
• HIV infection
  - In advanced HIV infection and neutropenia (ANC <1 x 10⁹/l 

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Severe renal impairment (CrCl <30ml/min) 
• Severe hepatic impairment
• When used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens
• Severe congenital neutropenia (Kostmann’s syndrome) with abnormal cytogenetics

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Elderly
• When used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens
• Severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution
• History of hypersensitivity to filgrastim or pegfilgrastim
• Myelodysplastic syndrome or chronic myelogenous leukaemia
• Acute myeloid leukaemia (AML)
  - Secondary AML
  - de novo AML patients aged <55 years with good cytogenetics [t (8; 21), t (15; 17), and inv (16)]
• Underlying osteoporotic bone diseases
• Recent history of pulmonary infiltrates or pneumonia
• High dose chemotherapy
• Substantially reduced myeloid progenitors
• Very extensive prior myelosuppressive therapy
• Normal donors <16 years or >60 years
• Donors who are anticoagulated or who have known defects in haemostasis
• Long-term treatment (of patients with SCN)
• Causes of transient neutropenia, such as viral infections
• Neonates
• Autoimmune neutropenia
• Neutropenia due to bone marrow-infiltrating infection or malignancy
• Patients with sickle cell trait or sickle cell disease
• Single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia
• Coadministration with haematopoietic growth factors and cytokines
• Hereditary fructose intolerance (HFI)
  - Babies and young children (below 2 years of age) (See additional prescribing points) 
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Elderly
• Pulmonary toxicity
• Sickle cell disease
• High dose chemotherapy
• Rheumatoid arthritis
• Pre-existing skin disorders, such as psoriasis
• Long term use
• Myelodysplastic syndrome or chronic myelogenous leukaemia
• Underlying osteoporotic bone disease
• Substantially reduced myeloid progenitors
• Graft versus Host Disease (GvHD)
• Long-term treatment (of patients with SCN)
• Causes of transient neutropenia, such as viral infections
• Neonates
• Patients with auto-immune neutropenia of infancy
• Patients who have undergone very extensive prior myelosuppressive therapy
• Donors who are anticoagulated or who have known defects in haemostasis
• Normal donors <16 years or >60 years
• Patients with known bone marrow infiltrating infection or malignancy
• Coadministration with haematopoietic growth factors and cytokines
• Hereditary fructose intolerance (HFI)

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

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) 
- In patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia
Mobilisation of peripheral blood progenitor cell (PBPCs)
Severe congenital, cyclic, or idiopathic neutropenia 
- In patients with an absolute neutrophil count (ANC) of ≤0.5 x 10⁹/l and a history of severe or recurrent infections to increase neutrophil counts and to reduce the incidence and duration of infection-related events
Neutropenia in HIV infection
- Persistent neutropenia (ANC ≤1.0 x 10⁹/l) in patients with advanced HIV infection to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate 

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Consult specialist for dosages and regimens

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South African manufacturer recommendations

Used for the treatment of

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) 
- In patients undergoing myeloablative therapy followed by bone marrow transplantation (for the reduction of neutropenia and its clinical sequelae)
Severe chronic neutropenia (SCN) 
- In patients with severe congenital, cyclic, or idiopathic neutropenia with an ANC ≤0,5x10⁹/l to increase neutrophil count and to reduce the incidence and duration of infections
Mobilisation of peripheral blood progenitor cell (PBPCs)
   - For the mobilisation of autologous PBPCs alone, or following myelosuppressive chemotherapy (in order to accelerate haematopoietic recovery by infusion of such cells after myelosuppressive or myeloablative therapy) 
- For the mobilisation of peripheral blood progenitor cells in normal donors (allogeneic) PBPC
HIV infection
- In advanced HIV infection and neutropenia (ANC <1 x 10⁹/l) to allow scheduled dosing of antiretroviral medication

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Consult specialist for dosages and regimens

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

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) 
- In patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. 
Severe congenital, cyclic, or idiopathic neutropenia 
- In patients with an absolute neutrophil count (ANC) of ≤0.5 x 10⁹/l and a history of severe or recurrent infections to increase neutrophil counts and to reduce the incidence and duration of infection-related events

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Consult specialist for dosages and regimens

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65% of patients studied in a severe chronic neutropenia (SCN) trial program were under 18 years of age. The efficacy of the treatment was clear for this age group, which included most patients with congenital neutropenia. There were no differences in the safety profiles for paediatric patients treated for SCN 

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Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy 

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The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy 

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South African manufacturer recommendations

Used for the treatment of

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) 
- In patients undergoing myeloablative therapy followed by bone marrow transplantation (for the reduction of neutropenia and its clinical sequelae)
Severe chronic neutropenia (SCN)
- In patients with severe congenital, cyclic, or idiopathic neutropenia with an ANC ≤0,5x10⁹/l to increase neutrophil count and to reduce the incidence and duration of infections

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Consult specialist for dosages and regimens

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Paediatric use in severe chronic neutropenia and cancer: 
- 65% of the patients studied in the severe chronic neutropenia (SCN) trial program were <18 years old. The efficacy of treatment was clear for this age group, which included most patients with congenital neutropenia. There were no differences in the safety profiles for paediatric patients treated for severe chronic neutropenia 

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Use in severe chronic neutropenia:
- The safety and efficacy in neonates have not been established 

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The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy 

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Peripheral blood progenitor cell mobilisation:
- The safety and efficacy of filgrastim have not been assessed in normal donors <16 years undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation

Pregnancy

International manufacturer recommendations

• Caution; not recommended 
• There are no or limited amount of data from the use of filgrastim in pregnant women. Studies in animals have shown reproductive toxicity. An increased incidence of embryo-loss has been observed in rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated
• Filgrastim is not recommended during pregnancy

South African manufacturer recommendations

• Caution; not recommended 
• The safety of filgrastim in pregnant women has not been established 
• There are reports in the literature that transplacental passage of filgrastim in pregnant women has been demonstrated. Studies in animals have shown reproductive toxicity. In pregnancy, the possible risk of filgrastim use to the foetus must be weighed against the expected therapeutic benefit. Filgrastim should not be used in pregnancy 

Breastfeeding

International manufacturer recommendations

• Caution
• It is unknown whether filgrastim or its metabolites are excreted in human milk. A risk to the breastfeeding child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from filgrastim therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

South African manufacturer recommendations

• Caution; not recommended 
• The safety of filgrastim in breastfeeding women has not been established 
• It is not known whether filgrastim is excreted in human milk. Women on filgrastim should not breastfeed their babies 

Fertility

International manufacturer recommendations

• Filgrastim did not affect reproductive performance or fertility in male or female rats 

South African manufacturer recommendations

• No information available 

Renal Impairment

International manufacturer recommendations

• No dose adjustment recommended

South African manufacturer recommendations

• Mild to moderate (CrCl ≥30ml/min): No dose adjustment recommended 
  Studies of filgrastim in patients with moderate impairment of renal function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals
• Severe (CrCl <30ml/min): Contraindicated 
  Studies have not been performed in patients with severe impairment of renal function and therefore its use in this patient group cannot be recommended
  Higher systemic exposure to filgrastim is observed in patients with end-stage renal disease (ESRD) compared with healthy subjects and subjects with creatinine clearance of 30-60ml/min

Hepatic Impairment

International manufacturer recommendations

• No dose adjustment recommended

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Contraindicated
  Studies have not been performed in patients with severe impairment of hepatic function and therefore its use in this patient group cannot be recommended

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Insomnia
• Headache
• Dizziness
• Hypoaesthesia
• Paraesthesia
• Fatigue

Cardiovascular Disorders 

• Hypotension
• Hypertension
• Veno-occlusive disease
• Aortitis
• Capillary leak syndrome

Respiratory Disorders 

• Oropharyngeal pain
• Cough
• Dyspnoea
• Haemoptysis
• Epistaxis
• Acute respiratory distress syndrome
• Chest pain
• Respiratory failure
• Pulmonary oedema
• Interstitial lung disease
• Lung infiltration
• Pulmonary haemorrhage
• Bronchitis
• Upper respiratory tract infection
• Hypoxia

Gastrointestinal Disorders 

• Diarrhoea
• Nausea and vomiting 
• Constipation
• Oral pain

Hepatobiliary Disorders 

• Increased gamma-glutamyl transferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Hepatomegaly

Genitourinary Disorders

• Dysuria
• Urine abnormality
• Glomerulonephritis
• Haematuria 
• Proteinuria
• Urinary tract infection

Endocrine and Metabolic Disorders

• Hyperuricaemia
• Increased blood lactate dehydrogenase
• Decreased appetite
• Decreased blood glucose
• Pseudogout (chondrocalcinosis pyrophosphate)
• Fluid volume disturbances
• Increased blood uric acid

Musculoskeletal Disorders

• Musculoskeletal pain
  - Bone pain
  - Back pain
  - Arthralgia
  - Myalgia
  - Pain in extremity
  - Musculoskeletal chest pain
  - Neck pain
• Exacerbation of rheumatoid arthritis
• Muscle spasms
• Osteoporosis
• Decreased bone density

Skin and Subcutaneous Tissue Disorders 

• Rash
  - Maculopapular rash
• Alopecia
• Erythema
• Sweets syndrome (acute febrile neutrophilic dermatosis)
• Cutaneous vasculitis
• Mucosal inflammation
• Injection site reaction

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
  - Anaphylaxis 
  - Rash
  - Urticaria
  - Angioedema
  - Dyspnoea 
  - Hypotension
• Drug hypersensitivity
• Anaphylactic reaction
• Fever
• Graft versus Host Disease
• Sepsis
• Thrombocytopenia
• Anaemia
• Decreased haemoglobin
• Leukocytosis
• Sickle cell anaemia with crisis
• Splenic rupture
• Splenomegaly
• Transformation to myelodysplastic syndrome or leukaemia (in SCN patients)
• Peripheral oedema
• Transfusion reaction

Others

• Pain 

• Myelosuppressive cytotoxic chemotherapy (See additional prescribing points) 
• 5-Fluorouracil
• Lithium (See additional prescribing points) 

Other interactions

• Bone-imaging scans (See additional prescribing points)

• Full blood count with differential 
• Platelet count 
• Haematocrit
• Haematopoietic progenitor cells

Specific cases may require

• Bone marrow 
• Bone density
• Karyotype
• Cytogenetics 

Additional observations

• Signs and symptoms of:
  - Allergic reactions
  - Aortitis
  - Capillary leak syndrome
  - Cutaneous vasculitis
  - Respiratory distress syndrome
  - Splenic rupture
  - Haematuria or proteinuria

Injection 30MU/0.5ml pre-filled syringe, Injection pre-filled syringe 48MU/0.5ml - EML Tertiary

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Traceability

• In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient file

Coadministration with myelosuppressive cytotoxic chemotherapy

• The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxic chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small number of patients treated concomitantly with filgrastim and 5-fluorouracil indicates that the severity of neutropenia may be exacerbated

Coadministration with lithium

• Since lithium promotes the release of neutrophils, lithium is likely to potentiate the effect of filgrastim. Although this interaction has not been formally investigated, there is no evidence that such an interaction is harmful 

Filgrastim causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some severe chronic neutropenia (SCN) patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. 

Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. 

Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into peripheral blood. These autologous peripheral blood progenitor cells (PBPCs) may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions. Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation. 

Injection (per 1ml) 30 MU

• Neupogen 30 (Amgen) originator

Injection (per 0.5ml) 30 MU

• Filgrastim Teva (Teva)
• Grastiva 300 (Accord Healthcare)
• Neupogen 30MU pre-filled syringe (Amgen) originator
• Zarzio (Sandoz)

Injection (per 0.5ml) 48 MU

• Filgrastim Teva (Teva)
• Grastiva 480 (Accord Healthcare)
• Neupogen 48MU pre-filled syringe (Amgen) originator
• Zarzio (Sandoz)