Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name of the administered product should be clearly recorded. It is recommended to record the batch number as well.

Special warnings 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 may be at higher risk.
The onset of pulmonary signs such as cough, fever and dyspnea 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 granulocytecolonystimulating factor administration, and is characterised by hypotension, hypoalbuminaemia, edema and hemoconcentration. 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 section 4.8).

Splenomegaly and splenic rupture
Generally asymptomatic cases of splenomegaly and 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 leukemia
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or chronic myelogenous leukemia 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 leukemia from acute myeloid leukemia.

Acute myeloid leukemia
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 × 109/L).

Leukocytosis
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 leukocytosis have been reported. However, in view of the potential risks associated with severe leukocytosis, a white blood cell count should be performed at regular intervals during filgrastim therapy. If leukocyte counts exceed 50 x 109/L after the expected nadir, filgrastim should be discontinued immediately. When administered for PBPC mobilization , filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to > 70 x 109/L.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. Rates 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 neutralizing 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 section 4.8.

Special warnings 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 tumor outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please 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 anemia 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 anemia. Regular monitoring of platelet count and hematocrit 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 mobilized PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.

Myelodysplastic syndrome and acute myeloid leukemia in breast and lung cancer patients In the post-marketing observational study setting, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been associated with the use of pegfilgrastim, an alternative G-CSF medicine, in conjunction with chemotherapy and/or radiotherapy in breast and lung cancer patients. A similar association between filgrastim and MDS/AML has not been observed. Nonetheless, patients with breast cancer and patients with lung cancer should be monitored for signs and symptoms of MDS/AML.

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 tumor).

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 section 4.8 and 5.1).

Increased hematopoietic 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 mobilization
Mobilization
There are no prospectively randomised comparisons of the two recommended mobilization 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 mobilization 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 mobilization 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 hematopoietic progenitor pool and may adversely affect progenitor mobilization . Agents such as melphalan, carmustine (BCNU) and carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilization , may reduce progenitor yield. However, the administration of melphalan, carboplatin or carmustine (BCNU) together with filgrastim has been shown to be effective for progenitor mobilization . When peripheral blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell mobilization procedure early in the treatment course of the patient. Particular attention should be paid to the number of progenitors mobilized in such patients before the administration of high-dose chemotherapy. If yields are inadequate, as measured by the criteria above, 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 flow cytometric 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 hematologic reconstitution. Yields in excess of this appear to correlate with more rapid recovery; those below with slower recovery.

Special precautions in normal donors undergoing peripheral blood progenitor cell mobilization 
Mobilization 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 mobilization should be considered only in donors who meet normal clinical and laboratory eligibility criteria for stem cell donation with special attention to h ematological values and infectious diseases.

The safety and efficacy of filgrastim have not been assessed in normal donors less than 16 years or greater than 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 are < 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 mobilization should be monitored until hematological indices return to normal.

Special precautions in recipients of allogeneic PBPC mobilized 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 leukemia or have evidence of leukemic evolution.

Blood cell counts
Other blood cell changes occur, including anemia and transient increases in myeloid progenitors, which require close monitoring of cell counts.

Transformation to leukemia or myelodysplastic syndrome
Special care should be taken in the diagnosis of SCNs to distinguish them from other hematopoietic disorders such as aplastic anemia, myelodysplasia and myeloid leukemia. 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 leukemia in clinical trial patients with SCN treated with filgrastim. This observation has only been made in patients with congenital neutropenia. MDS and leukemias 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 leukemic 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.

Hematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis should be performed to monitor this event.

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 to 3 days of filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice weekly 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 microgram)/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 taken for 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 anemia 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 anemia. Regular monitoring of blood counts is recommended (see above).

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

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

StimoFil contains D-sorbitol as an excipient at a concentration of 50 mg/ml. 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 lifethreatening 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.

StimoFil contains less than 1mmol (23 mg) sodium per dose, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

StimoFil may have a minor influence on the ability to drive and use machines.

Dizziness may occur following the administration of StimoFil (see section 4.8).