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Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Special warning and precautions across indications: Hypersensitivity: Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.
Pulmonary adverse effects: Pulmonary adverse effects, in particular interstitial lung disease, have been reported after G-CSF administration. Patients with a recent history of lung infiltrates or pneumonia maybe at higher risk. The onset of pulmonary signs, such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment given.
Glomerulonephritis: Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Capillary leak syndrome: Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported after granulocyte colony-stimulating factor administration, and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration.
Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see Adverse Reactions).
Splenomegaly and splenic rupture: Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported in patients and normal donors following administration of filgrastim. Some cases of splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper abdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop the progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a splenectomy was required.
Malignant cell growth: Granulocyte colony-stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro.
Myelodysplastic syndrome or Chronic myeloid leukaemia: The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome, or chronic myelogenous leukaemia have not been established. Filgrastim is not indicated for use in these conditions. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
Acute myeloid leukaemia: In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be administered with caution. The safety and efficacy of filgrastim administration in de novo AML patients aged <55 years with good cytogenetics (t(8;21), t(15;17), and inv(16)) have not been established.
Thrombocytopenia: Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic neutropenia who develop thrombocytopenia (platelet count <100 x 109/L).
Leucocytosis: White blood cell counts of 100 x 109/L or greater have been observed in less than 5% of cancer patients receiving filgrastim at doses above 0.3 MU/kg/day (3 μg/kg/day). No undesirable effects directly attributable to this degree of leucocytosis have been reported. However, in view of the potential risks associated with severe leucocytosis, a white blood cell count should be performed at regular intervals during filgrastim therapy. If leucocyte counts exceed 50 x 109/L after the expected nadir, filgrastim should be discontinued immediately. When administered for PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leucocyte counts rise to >70 x 109/L.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Rate of generation of antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present.
Aortitis: Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases, aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF (see Adverse Reactions).
Special warning and precautions associated with co-morbidities: Special precautions in sickle cell trait and sickle cell disease: Sickle cell crises, in some cases fatal, have been reported with the use of filgrastim in patients with sickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim in patients with sickle cell trait or sickle cell disease.
Osteoporosis: Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with filgrastim for more than 6 months.
Special precautions in cancer patients: Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Risks associated with increased doses of chemotherapy: Special caution should be used when treating patients with high dose chemotherapy, because improved tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead to increased toxicities including cardiac, pulmonary, neurologic, and dermatologic effects (refer to the prescribing information of the specific chemotherapy agents used).
Effect of chemotherapy on erythrocytes and thrombocytes: Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy (e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions: The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil counts. Therefore, in patients with reduced precursors neutrophil response may be diminished (such as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration by tumour).
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported occasionally in patients undergoing high dose chemotherapy followed by transplantation.
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient abnormal bone scans. This should be considered when interpreting bone-imaging results.
Special precautions in patients undergoing PBPC mobilisation: Mobilisation: There are no prospectively randomised comparisons of the two recommended mobilisation methods (filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patient population. The degree of variation between individual patients and between laboratory assays of CD34+ cells mean that direct comparison between different studies is difficult. It is therefore difficult to recommend an optimum method. The choice of mobilisation method should be considered in relation to the overall objectives of treatment for an individual patient.
Prior exposure to cytotoxic agents: Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient mobilisation of PBPC to achieve the recommended minimum yield (≥2.0 x 106 CD34+ cells/kg) or acceleration of platelet recovery, to the same degree.
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool, and may adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU), and carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU together with filgrastim has been shown to be effective for progenitor mobilisation. When a PBPC transplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in the treatment course of the patient. Particular attention should be paid to the number of progenitors mobilised in such patients before the administration of high-dose chemotherapy. If yields are inadequate, as measured by the criteria previously mentioned, alternative forms of treatment, not requiring progenitor support should be considered.
Assessment of progenitor cell yields: In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular attention should be paid to the method of quantitation. The results of flowcytometric analysis of CD34+ cell numbers vary depending on the precise methodology used and recommendations of numbers based on studies in other laboratories need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.
The recommendation of a minimum yields of ≥2.0 x 106 CD34+ cells/kg is based on published experience resulting in adequate haematologic reconstitution. Yields in excess of this appear to correlate with more rapid recovery, those below with slower recovery.
Special precautions in normal donors undergoing PBPC mobilisation: Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory eligibility criteria for stem cell donation with special attention to haematological values and infectious disease.
The safety and efficacy of filgrastim have not been assessed in normal donors <16 years or >60 years.
Transient thrombocytopenia (platelets <100 x 109/L) following filgrastim administration and leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets <50 x 109/L were reported and attributed to the leukapheresis procedure.
If more than one leukapheresis is required, particular attention should be paid to donors with platelets <100 x 109/L prior to leukapheresis; in general apheresis should not be performed if platelets <75 x 109/L.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices return to normal.
Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The significance of these changes is unknown. Nevertheless, a risk of promotion of a malignant myeloid clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
Special precautions in recipients of allogeneic PBPCs mobilised with filgrastim: Current data indicate that immunological interactions between the allogeneic PBPC graft and the recipient may be associated with an increased risk of acute and chronic GvHD when compared with bone marrow transplantation.
Special precautions in SCN patients: Filgrastim should not be administered to patients with severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution.
Blood cell counts: Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, which require close monitoring of cell counts.
Transformation to leukaemia or myelodysplastic syndrome: Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic disorders such as aplastic anaemia, myelodysplasia, and myeloid leukaemia. Complete blood cell counts with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype should be performed prior to treatment.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in clinical trial patients with SCN treated with filgrastim. This observation has only been made in patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including monosomy 7, on routine repeat evaluation. It is currently unclear whether long-term treatment of patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic transformation. It is recommended to perform morphologic and cytogenetic bone marrow examinations in patients at regular intervals (approximately every 12 months).
Other special precautions: Causes of transient neutropenia, such as viral infections should be excluded.
Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis should be performed to monitor these events.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
Special precautions in patients with HIV infection: Blood cell counts: Absolute neutrophil count (ANC) should be monitored closely, especially during the first few weeks of filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil count to the initial dose of filgrastim. It is recommended that the ANC is measured daily for the first 2-3 days of filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice per week for the first two weeks and subsequently once per week or once every other week during maintenance therapy. During intermittent dosing with 30 MU (300 μg)/day of filgrastim, there can be wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or nadir ANC, it is recommended that blood samples are takenf or ANC measurement immediately prior to any scheduled dosing with filgrastim.
Risk associated with increased doses of myelosuppressive medicinal products: Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive medications. As a result of the potential to receive higher doses or a greater number of these medications with filgrastim therapy, the patient may be at higher risk of developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see previously mentioned).
Infections and malignancies causing myelosuppression: Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. In patients with known bone marrow infiltrating infections or malignancy, consider appropriate therapy for treatment of the underlying condition, in addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on neutropenia due to bone marrow infiltrating infection or malignancy have not been well established.
All patients: Nivestim contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary.
Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and should be contraindicated in this population unless there is an overwhelming clinical need and no alternatives are available.
A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per 0.6 mg/ml or 0.96 mg/ml dose, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Nivestim may have a minor influence on the ability to drive and use machines. Dizziness may occur following the administration of filgrastim (see Adverse Reactions).
