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Pre-filled syringe (Solution for injection or infusion)
Pre-filled syringe (Solution for injection or infusion)
Established cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of StimoFil should not be administered less than 24 hours following cytotoxic chemotherapy. In randomised clinical trials, a subcutaneous dose of 230 microgram/m2/day (4.0 to 8.4 microgram/kg/day) was used.
Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Following established chemotherapy for solid tumours, lymphomas, and lymphoid leukaemias, it is expected that the duration of treatment required to fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on the type, dose and schedule of cytotoxic chemotherapy used.
In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1-2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to the time of the expected neutrophil nadir, is not recommended.
In patients treated with myeloablative therapy followed by bone marrow transplantation:
The recommended starting dose of filgrastim is 1.0 MU/kg/day (10 micrograms/kg/day). The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.
For Mobilisation of peripheral blood progenitor cells (PBPC) in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MU (10 µg)/kg/day for 5-7 consecutive days. The timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Filgrastim dosing should be maintained until the last leukapheresis. The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 0.5 MU (5 µg)/kg/day given daily from the first day after completion of chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis should be performed during the period when the ANC rises from < 0.5 x 109 /L to > 5.0 x 109 /L. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended.
For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation:
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MU (10 µg)/kg/day for 4 – 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order to collect 4 x 106CD34+ cells/kg recipient bodyweight.
In patients with severe chronic neutropenia (SCN)
Congenital neutropenia: The recommended starting dose is 1.2 MU (12 µg)/kg/day as a single dose or in divided doses.
Idiopathic or cyclic neutropenia: The recommended starting dose is 0.5 MU (5 µg)/kg/day as a single dose or in divided doses.
Dose adjustments: Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 x 109 /L. When the response has been obtained, the minimal effective dose to maintain this level should be established. Long-term daily administration is required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose may be doubled or halved depending upon the patient’s response. Subsequently, the dose may be individually adjusted every 1-2 weeks to maintain the average neutrophil count between 1.5 x 109 /L and 10 x 109 /L. A faster schedule of dose escalation may be considered in patients presenting with severe infections.
In clinical studies, 97% of patients who responded had a complete response at doses of ≤ 24 µg/kg/day. The long-term safety of administration of filgrastim at doses above 24 µg/kg/day in patients with SCN has not been established.
In patients with HIV infection
For reversal of neutropenia: The recommended starting dose of filgrastim is 0.1 MU (1 µg)/kg/day, given daily with titration up to a maximum of 0.4 MU (4 µg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC > 2.0 x 109 /L). In clinical studies, more than 90% of patients responded at these doses, achieving a reversal of neutropenia in a median of 2 days. In a small number of patients (< 10%), doses up to 1.0 MU (10 µg)/kg/day were required to achieve reversal of neutropenia.
For maintenance of normal neutrophil counts:
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MU (300 µg)/day is recommended. Further dose adjustment may be necessary, as determined by the patient’s ANC, to maintain the neutrophil count at > 2.0 x 109 /L. In clinical studies, dosing with 30 MU (300 µg)/day on 1 – 7 days per week was required to maintain the ANC > 2.0 x 109 /L, with the dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC > 2.0 x 109 /L.
Clinical trials with filgrastim have included a small number of elderly patients but special studies have not been performed in this group and therefore specific posology recommendations cannot be made.
Patients with renal impairment
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals.
Dose adjustment is not required in these circumstances.
Paediatric patients in the SCN and cancer settings
Sixty-five percent of patients studied in a 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.
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.
The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy.
Method of administration
Established cytotoxic chemotherapy
Filgrastim may be administered as a daily subcutaneous injection or alternatively as a daily intravenous infusion diluted in glucose 50 mg/ml (5%) solution over 30 minutes. For further instructions on dilution prior to infusion. The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose administration that intravenous dosing may shorten the duration of effect. The clinical relevance of this finding to multiple dose administration is not clear. The choice of route should depend on the individual clinical circumstance. Patients treated with myeloablative therapy followed by bone marrow transplantation.
Filgrastim is administered as an intravenous short-term infusion over 30 minutes or as a subcutaneous or intravenous continuous infusion over 24 hours, in each case after dilution in 20 ml of glucose 50 mg/ml (5%) solution. For further instructions on dilution with glucose 50 mg/ml (5%) solution prior to infusion.
In patients with Mobilisation of PBPC
Filgrastim for PBPC mobilisation when used alone:
Filgrastim may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For infusions filgrastim should be diluted in 20 ml of 5% glucose solution.
Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy:
Filgrastim should be given by subcutaneous injection.
For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation
Filgrastim should be given by subcutaneous injection.
In patients with SCN
Congenital, idiopathic or cyclic neutropenia; filgrastim should be given by subcutaneous injection.
In patients with HIV infection
For the reversal of neutropenia and maintenance of normal neutrophil counts in patients with HIV infection, filgrastim is administered subcutaneously.
StimoFil is indicated for the 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) and for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and efficacy of StimoFil are similar in adults and children receiving cytotoxic chemotherapy.
StimoFil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs).
In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of ≤ 0.5 x 109 /L, and a history of severe or recurrent infections, long term administration of StimoFil is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
StimoFil is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.
Hypersensitivity to the active substance or to any of the excipients.
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Filgrastim should not be administered to patients with severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution.
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.
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 neutralising activity at present.
Special precautions in patients with acute myeloid leukaemia (AML)
Malignant cell growth
G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some nonmyeloid cells in vitro.
Myelodysplastic syndrome or Chronic myeloid leukemia
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or chronic myelogenous leukaemia have not been established. Therefore, 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.
White blood cell counts of 100 x 109/L or greater have been observed in less than 5% of patients receiving filgrastim at doses above 0.3 MIU/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. However, during the period of administration of filgrastim for PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to > 70 x 109/L.
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 (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 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.
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 boneimaging results.Special precautions in patients undergoing PBPC mobilization
Mobilization of PBPC
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 optimal 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 carmustine (BCNU) together with filgrastim has been shown to be effective for progenitor mobilisation. When peripheral blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell.
The number of progenitors mobilised 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 therefore, 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 yield of ≥ 2.0 x 106 CD34+ cells/kg is based on published experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield appear to correlate with more rapid recovery; those below with slower recovery.
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilization 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. Particular attention should be paid to haematological values and infectious diseases. The safety and efficacy of filgrastim has not been assessed in normal donors less than 16 years or greater than 60 years of age.
Thrombocytopenia has been reported very commonly in patients receiving filgrastim. Platelet counts should therefore be monitored closely.
Special precautions in recipients of allogeneic PBPC 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
Blood cell counts
Thrombocytopenia has been reported commonly in patients receiving filgrastim. Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm3.
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.
Other special precautions
Causes of transient neutropenia such as viral infections should be excluded. Cases of splenomegaly have been reported very commonly and cases of splenic rupture have been reported commonly following administration of filgrastim. Individuals receiving filgrastim who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.
Special precautions in patients with HIV infection
Cases of splenomegaly have been reported commonly following administration of filgrastim.
Individuals receiving filgrastim who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.
Blood cell counts
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 anaemia due to
myelosuppressive medicinal products. As a result of the potential to receive higher doses or a greater number of these medicinal products with filgrastim therapy, the patient may be at higher risk of developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended.
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. Special precautions in sickle cell trait and sickle cell disease.
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with sickle cell trait or sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in patients with sickle cell trait or sickle cell disease and only after careful evaluation of the potential risks and benefits.
See prescribing information for full details.
Dehydrogenase increased, headache dizziness, hypoesthesia, paraesthesia, hypotension, hypertension, haemoptysis, dyspnoea, cough, oropharyngeal pain, epistaxis, diarrhea, vomiting, nausea, constipation, oral pain, blood alkaline, phosphatase, increased, hepatomegal, alopecia, rash, erythema, musculoskeletal pain, muscle spasms, dysuria, haematuria, fatigue, mucosal, inflammation, pyrexia, chest pain, asthenia, pain, malaise, oedema, peripheral, transfusion reaction, sepsis, bronchitis upper, respiratory tract, infection, urinary tract infection. See prescribing information for full details.
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.
Possible interactions with other haematopoietic growth factors and cytokines have not yet been investigated in clinical trials.
Since lithium promotes the release of neutrophils, it 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.
Pregnancy and Lactation
There are no or limited data from the use of filgrastim in pregnant women. Filgrastim is not recommended during pregnancy. See prescribing information for full details.
It is unknown whether filgrastim/metabolites are excreted in human milk. A risk to the newborns/infants 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 breast feeding for the child and the benefit of therapy for the woman.
The effects of StimoFil overdose have not been established. Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels in 1 to 7 days.
Store in a refrigerator (2°C – 8°C). Do not freeze.
Accidental one-time exposure to freezing temperatures does not adversely affect the stability of StimoFil. If exposure has been greater than 24 hours or frozen more than once then StimoFil should NOT be used.
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 days. At the end of this period, the product should not be put back in the refrigerator and should be disposed of.
Keep the syringe in the outer carton in order to protect from light.
Special precautions for disposal and other handling
If required, StimoFil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU (2 μg) per ml is not recommended at any time.
The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Do not shake.
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 μg) per ml, human serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 μg) should be given with 0.2 ml of 200 mg/ml (20%) human albumin solution added.
StimoFil contains no preservative. In view of the possible risk of microbial contamination, StimoFil pre-filled syringes are for single use only.
When diluted in 5% glucose, StimoFil is compatible with glass and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.