Neupogen

Neupogen

filgrastim

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Filgrastim.
Description
Active Ingredient: filgrastim (recombinant-methionyl human granulocyte-colony stimulating factor, r-metHuG-CSF, from E. coli K12).
Filgrastim is a highly purified non-glycosylated protein comprising 175 amino acids. Filgrastim is produced in a laboratory strain of Escherichia coli bacteria which has been genetically altered by the addition of a gene for the granulocyte colony-stimulating factor.
Vials: 1 vial of Neupogen of 1.0 ml injection solution contains 30 MU (= 300 μg) of filgrastim.
1 vial of Neupogen of 1.6 ml injection solution contains 48 MU (= 480 μg) of filgrastim.
Pre-filled syringes: 1 pre-filled syringe of Neupogen of 0.5 ml contains 30 MU (= 300 μg) of filgrastim.
1 pre-filled syringe of Neupogen of 0.5 ml contains 48 MU (= 480 μg) of filgrastim.
Excipients/Inactive Ingredients: sodium acetate*, sorbitol, polysorbate 80, water for injection.
*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Human granulocyte-colony stimulating factor is a glycoprotein, which regulates the production and release of functional neutrophils from the bone marrow. Neupogen containing r-metHuG-CSF (filgrastim), causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some severe chronic neutropenia patients Neupogen 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 by the human body in response to Neupogen show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of Neupogen therapy, circulating neutrophil counts decrease by 50% within one to two days, and to normal levels within one to seven days.
Treatment with Neupogen in patients undergoing cytotoxic chemotherapy or myeloablative therapy followed by bone marrow transplantation leads to a significant reduction in the incidence, severity and duration of neutropenia and febrile neutropenia, and consequently, fewer admissions to the hospital, shorter duration of hospitalisation and less antibiotics as compared to patients on cytotoxic chemotherapy alone.
Treatment with Neupogen significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia. The incidence of fever and documented infections was not reduced in this setting.
Use of Neupogen, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into the peripheral blood. These autologous peripheral blood progenitor cells (PBPC) may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.
Recipients of allogeneic peripheral blood progenitor cells mobilised with Neupogen experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.
Use of Neupogen in patients, children or adults, with severe chronic neutropenia (severe congenital, cyclic and idiopathic neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a reduction of infection and related events. Use of Neupogen in patients with HIV infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with HIV infection treated with Neupogen show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
Pharmacokinetics: Absorption: After s.c. administration, filgrastim is rapidly absorbed, and peak serum concentrations are attained 2 to 8 hours after dosing. Elimination half-life after i.v. and s.c. dosing is usually between 2 and 4 hours. Clearance and half-life are dependent on dose and neutrophil count. When neutrophil-mediated clearance is saturated by high filgrastim concentrations or is diminished by neutropenia, the linear clearance pathway predominates and the pharmacokinetics appear linear. The absolute bioavailability of filgrastim after s.c. administration is estimated to be 62% for a 375 μg dose and 72% for a 750 μg dose. After discontinuation of dosing, filgrastim concentrations decrease to endogenous concentrations within 24 hours.
A decrease in filgrastim serum concentrations is evidenced upon multiple dosing in healthy subjects and in cancer subjects before chemotherapy. This increase in clearance of filgrastim is dose dependent, and the magnitude of increase appears closely related to the degree of neutrophilia in the recipients, which is consistent with increased neutrophil-mediated clearance by the expanded neutrophil pool. In subjects receiving filgrastim after chemotherapy, plateau serum concentrations are maintained until onset of haematopoietic recovery.
Distribution: There is a positive linear correlation between the dose and the serum concentration of Neupogen, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 ng/ml for 8 to 16 hours. The volume of distribution in blood is approximately 150 ml/kg.
Elimination: Continuous infusion with Neupogen over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives.
Clearance of Neupogen has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The mean serum elimination half-life of Neupogen is approximately 3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg.
Pharmacokinetics in Special Populations: Paediatrics: The pharmacokinetics of filgrastim in paediatric patients after chemotherapy is similar to those in adults receiving the same weight-normalised doses, suggesting no age-related differences in the pharmacokinetics of filgrastim.
Geriatrics: Pharmacokinetic data in geriatric patients (> 65 years) are not available.
Renal or hepatic 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. A trend towards higher systemic exposure to filgrastim is observed in patients with ESRD compared with healthy subjects and subjects with creatinine clearance of 30-60 ml/min.
Toxicology: Preclinical Safety: Carcinogenicity: The carcinogenic potential of filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolising enzyme system.
Certain malignant cells have been shown to express granulocyte-colony stimulating factor (G-CSF) receptors. The possibility that filgrastim can act as growth factor for any tumor type cannot be excluded.
Impairment of Fertility: Filgrastim had no observed effect on the fertility of male or female rats, or gestation, at doses up to 500 μg/kg.
Teratogenicity: There is no evidence from studies in rats and rabbits that Neupogen is teratogenic. An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been seen.
Indications/Uses
Established cytotoxic chemotherapy: Neupogen is indicated for 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 leukemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia and its clinical sequelae in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia (see Special Populations: Pediatric Use under Precautions).
Peripheral blood progenitor cell mobilization (PBPC): Neupogen is indicated for the mobilization of autologous peripheral blood progenitor cells alone, or following myelosuppressive chemotherapy and the mobilization of peripheral blood progenitor cells in normal donors (allogeneic PBPC).
Severe Chronic Neutropenia (SCN): Long term administration of Neupogen is indicated in patients, children or adults, with severe congenital, cyclic or idiopathic neutropenia with an Absolute Neutrophil Count (ANC) ≤ 0.5x109/l, and a history of severe or recurrent infections, to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
HIV infection: Neupogen is indicated for the treatment of persistent neutropenia (ANC ≤ 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.
Dosage/Direction for Use
Neupogen therapy should only be given in collaboration with an oncology center which has experience in G-CSF treatment and haematology and has the necessary diagnostic facilities.
The mobilisation and apheresis procedures should be performed in collaboration with an oncology haematology center with acceptable experience in this field and where the monitoring of haematopoietic progenitor cells can be correctly performed.
Established cytotoxic chemotherapy: The recommended dose of Neupogen is 0.5 MU (5 μg)/kg/day. The first dose of Neupogen should not be administered less than 24 hours following cytotoxic chemotherapy. Neupogen may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 5% glucose solution given over 30 minutes (see Cautions for Usage). 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 circumstances.
Daily dosing with Neupogen should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Following established chemotherapy for solid tumors, lymphomas, and lymphoid leukemia, it is expected that the duration of treatment required to fulfill these criteria will be up to 14 days. Following induction and consolidation treatment for acute myeloid leukemia 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 to 2 days after initiation of Neupogen therapy. However, for a sustained therapeutic response, Neupogen therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of Neupogen therapy, prior to the time of the expected neutrophil nadir, is not recommended.
For use in children see section Special Populations: Pediatric Use under Precautions.
In patients treated with myeloablative therapy followed by bone marrow transplantation: The recommended starting dose of Neupogen is 1.0 MU (10 μg)/kg/day given as a 30 minute or 24 hour intravenous infusion or 1.0 MU (10 μg)/kg/day given by continuous 24 hours subcutaneous infusion.
Neupogen should be diluted in 20 ml of 5% glucose solution (see Cautions for Usage).
The first dose of Neupogen should not be administered less than 24 hours following cytotoxic chemotherapy but within 24 hours of bone marrow infusion.
The efficacy and safety of Neupogen given for longer than 28 days in this setting have not been established.
Once the neutrophil nadir has been passed, the daily dose of Neupogen should be titrated against the neutrophil response as follows (see Special Populations: Pediatric Use under Precautions): (See Table 1.)

Click on icon to see table/diagram/image

Peripheral blood progenitor cell mobilization: Mobilization of Peripheral Blood Progenitor Cells (PBPC) in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation with or without bone marrow transplantation: The recommended dose of Neupogen for PBPC mobilization when used alone is 1.0 MU (10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection for 5 to 7 consecutive days. For infusions Neupogen should be diluted in 20 ml of 5% glucose solution (see Cautions for Usage). Timing of leukapheresis: one or two leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Neupogen dosing should be maintained until the last leukapheresis.
The recommended dose of Neupogen for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU (5 μg)/kg/day given daily by subcutaneous injection 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.
Mobilization of Peripheral Blood Progenitor Cells (PBPC) in normal donors prior to allogeneic peripheral blood progenitor cell transplantation: For PBPC mobilization in normal donors, Neupogen should be administered at 10 μg/kg/day subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipients bodyweight.
Severe chronic neutropenia (SCN): Congenital neutropenia: the recommended starting dose is 1.2 MU (12 μg)/kg/day subcutaneously as a single dose or in divided doses.
Idiopathic or cyclic neutropenia: the recommended starting dose is 0.5 MU (5 μg)/kg/day subcutaneously as a single dose or in divided doses.
Dose adjustment: Neupogen 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 to 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 trials, 97 % of patients who responded had a complete response at doses ≤ 24 μg/kg/day.
The long-term safety of Neupogen administration above 24 μg/kg/day in patients with severe chronic neutropenia has not been established.
For children see Special Populations: Pediatric Use under Precautions.
HIV Infection: For Reversal of Neutropenia: The recommended starting dose of Neupogen is 0.1 MU (1 μg)/kg/day given daily by subcutaneous injection 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, > 90% of patients responded at these doses, achieving 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 Maintaining 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 by subcutaneous injection 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 to 7 days per week was required to maintain the ANC >2.0 x 109/l, with the median dose frequency being 3 days per week. Long term administration may be required to maintain the ANC >2.0 x 109/l.
Special Dosage Instructions: Clinical trials with Neupogen have included a small number of elderly patients but special studies have not been performed in this group and therefore specific dosage recommendations cannot be made (see Special Populations: Geriatric Use under Precautions).
The dosage recommendations in pediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy (see Special Populations: Pediatric Use under Precautions).
Studies of Neupogen 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.
Overdosage
The effects of Neupogen overdosage have not been established.
Doses up to 138 μg/kg/day were administered to patients in BMT studies without toxic effects.
Discontinuation of Neupogen therapy usually results in a 50% decrease in circulating neutrophils within one to two days, with a return to normal levels in one to seven days.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Excipients/Inactive Ingredients under Description.
Special Precautions
General: Neupogen should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Neupogen 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 Neupogen. Permanently discontinue Neupogen in patients with clinically significant hypersensitivity. Do not administer Neupogen 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.
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 GCSF.
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.
The safety and efficacy of Neupogen administration in patients with myelodysplastic syndrome, or chronic myelogenous leukemia have not been established.
Neupogen 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.
In view of limited safety and efficacy data in patients with secondary AML, Neupogen should be administered with caution.
The safety and efficacy of Neupogen 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.
Other special precautions: Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with Neupogen for more than 6 months.
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 dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory distress syndrome (ARDS). Neupogen should be discontinued and appropriate treatment given.
Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration, and is characterised by hypotension, hypoalbuminaemia, oedema 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 Adverse Reaction).
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.
The needle cover of the pre-filled syringe may contain dry natural rubber (a derivative of latex), which may cause allergic reactions.
Special precautions in cancer patients: Cases of splenomegaly and splenic rupture have been reported uncommonly following administration of filgrastim. Some cases of splenic rupture were fatal. Individuals receiving filgrastim who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.
Leukocytosis: White blood cell counts of 100 x 109/l or greater have been observed in less than 5% of patients receiving Neupogen 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 Neupogen therapy. If leukocyte counts exceed 50 x 109/l after the expected nadir, Neupogen should be discontinued immediately. However, during the period of administration of Neupogen for PBPC mobilization, Neupogen 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).
Treatment with Neupogen 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 of 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 Neupogen mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions: The effects of Neupogen in patients with substantially reduced myeloid progenitors have not been studied. Neupogen 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 GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see Adverse Reactions).
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 (Neupogen 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 Neupogen, 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 previously mentioned criteria, 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 Neupogen, 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 yield 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 as follows 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 Neupogen have not been assessed in normal donors < 16 years or > 60 years.
Thrombocytopenia has been reported very commonly in patients receiving Neupogen. Platelet counts should therefore be monitored closely.
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 hemostasis.
Neupogen administration should be discontinued or its dosage should be reduced if the leukocyte counts rise to >70 x 109/l.
Donors who receive G-CSFs for PBPC mobilization should be monitored until hematological 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.
Common but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture have been reported in healthy donors (and patients) following administration of granulocyte-colony stimulating factors (G-CSFs). 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 pain or shoulder tip pain.
In normal donors, dyspnoea has been reported commonly and other pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, and hypoxia) have been reported uncommonly. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with Neupogen should be considered and appropriate medical care given.
Special precautions in recipients of allogeneic PBPCs mobilised with Neupogen: 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 Neupogen. Platelet counts should be monitored closely, especially during the first few weeks of Neupogen therapy. Consideration should be given to intermittent cessation or decreasing the dose of Neupogen 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.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in clinical trial patients with SCN treated with Neupogen. 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 Neupogen 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. If patients with severe chronic neutropenia develop abnormal cytogenetics, the risks and benefits of continuing Neupogen should be carefully weighed; Neupogen should be discontinued if MDS or leukaemia occur. 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.
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.
Splenomegaly is a direct effect of treatment with Neupogen. Thirty-one percent (31%) of patients in studies were documented as having palpable splenomegaly. Increases in volume, measured radiographically, occurred early during Neupogen therapy and tended to plateau. Dose reductions were noted to slow or stop the progression of splenic enlargement, and in 3% of patients a splenectomy was required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to detect abnormal increases in splenic volume.
Haematuria 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: Cases of splenomegaly have been reported commonly following administration of Neupogen. Individuals receiving filgrastim who report left upper abdominal and/or shoulder tip pain should therefore be evaluated for an enlarged spleen or splenic rupture.
Blood cell counts: Absolute neutrophil count (ANC) should be monitored closely, especially during the first few weeks of Neupogen therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil count to the initial dose of Neupogen. It is recommended that the ANC is measured daily for the first 2-3 days of Neupogen 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 Neupogen, 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 Neupogen.
Risk associated with increased doses of myelosuppressive medications: Treatment with Neupogen 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 Neupogen therapy, the patient may be at higher risk of developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see previously mentioned text).
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 Neupogen for treatment of neutropenia. The effects of Neupogen 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 cell crises, in some cases fatal, have been reported with the use of Neupogen in patients with sickle cell trait or sickle cell disease. Physicians should use caution when prescribing Neupogen in patients with sickle cell trait or sickle cell disease.
All patients: Neupogen contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Neupogen vial contains less than 1 mmol (23 mg) sodium per 0.3 mg/ml, i.e. essentially sodium free.
Neupogen (30 MU) pre-filled syringe contains less than 1 mmol (23 mg) sodium per 0.6 mg/ml, i.e. essentially sodium free.
Neupogen (48 MU) pre-filled syringe contains less than 1 mmol (23 mg) sodium per 0.96 mg/ml, i.e. essentially sodium free.
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.
Renal Impairment: See Special Dosage Instructions under Dosage & Administration.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration.
Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
Paediatric Use: Established cytotoxic chemotherapy: The safety and efficacy of Neupogen are similar in adults and children receiving cytotoxic chemotherapy.
In patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation: The safety and efficacy of Neupogen have not been assessed in normal donors < 16 years.
In patients with severe chronic neutropenia (SCN): The safety and efficacy in neonates have not been established.
Long term administration of Neupogen is indicated in children with severe congenital, cyclic or idiopathic neutropenia with an Absolute Neutrophil Count (ANC) ≤ 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 (see Special Dosage Instructions under Dosage & Administration).
Paediatric use in the SCN and cancer settings: Sixty-five percent of patients studied in the SCN trial program were under 18 years of age. 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.
Geriatric Use: In patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation: The safety and efficacy of Neupogen have not been assessed in normal donors > 60 years.
Use In Pregnancy & Lactation
Pregnancy: The safety of Neupogen has not been established in pregnant women. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated (see Pharmacology: Toxicology: Teratogenicity under Actions). Studies in animals have shown reproductive toxicity. In pregnancy, the possible risk of Neupogen use to the fetus must be weighed against the expected therapeutic benefit.
Nursing Mothers: It is not known whether Neupogen is excreted in human milk. Neupogen is not recommended for use in nursing women.
Adverse Reactions
Clinical Trials: Summary of the safety profile: In clinical trials in cancer patients the most frequent undesirable effect was musculoskeletal pain which was mild or moderate in 10%, and severe in 3% of patients.
Graft versus Host Disease (GvHD) has also been reported (see Description of selected adverse reactions as follows).
In PBPC mobilisation in normal donors the most commonly reported undesirable effect was musculoskeletal pain. Leukocytosis was observed in donors and thrombocytopenia following filgrastim and leukapheresis was also observed in donors. Splenomegaly and splenic rupture were also reported. Some cases of splenic rupture were fatal.
In SCN patients the most frequent undesirable effects attributable to Neupogen were bone pain, general musculoskeletal pain and splenomegaly. Myelodysplastic syndromes (MDS) or leukaemia have developed in patients with congenital neutropenia treated with Neupogen (see Precautions).
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported uncommonly (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy and healthy donors undergoing peripheral blood progenitor cell mobilisation following administration of granulocyte-colony stimulating factors; see Precautions and Description of selected adverse reactions as follows.
In clinical studies in patients with HIV, the only undesirable effects that were consistently considered to be related to Neupogen administration were musculoskeletal pain, bone pain and myalgia.
Tabulated summary of adverse reactions: Cancer patients: (See Table 2.)

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PBPC mobilisation in normal donors: (See Table 3.)

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SCN patients: (See Table 4.)

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Patients with HIV: (See Table 5.)

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Description of selected adverse reactions: There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see Precautions).
Cases of capillary leak syndrome have been reported in the post-marketing setting with granulocyte-colony stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis (see Precautions).
Cancer patients: In randomised, placebo-controlled clinical trials, Neupogen did not increase the incidence of undesirable effects associated with cytotoxic chemotherapy. In those clinical trials, undesirable effects reported with equal frequency in patients treated with Neupogen/chemotherapy and placebo/chemotherapy included nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia (decreased appetite), mucosal inflammation, headache, cough, rash, chest pain, asthenia, pharyngolaryngeal pain (oropharyngeal pain) and constipation.
In the post-marketing setting cutaneous vasculitis has been reported in patients treated with Neupogen. The mechanism of vasculitis in patients receiving Neupogen is unknown. The frequency is estimated as uncommon from clinical trial data.
Cases of Sweets syndrome (acute febrile dermatosis) has been reported in the post-marketing setting. The frequency is estimated as uncommon from clinical trial data.
In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung disease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome of respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see Precautions).
Cases of splenomegaly and splenic rupture have been reported uncommonly following administration of filgrastim. Some cases of splenic rupture were fatal (see Precautions).
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in post marketing experience. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Neupogen should be permanently discontinued in patients who experience a serious allergic reaction.
In the post-marketing setting, isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (see Precautions). The frequency is estimated as uncommon from clinical trial data.
Pseudogout has been reported in patients with cancer treated with Neupogen. The frequency is estimated as uncommon from clinical trial data.
PBPC mobilisation in normal donors: Common but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture have been reported in healthy donors and patients following administration of filgrastim. Some cases of splenic rupture were fatal (see Precautions).
Pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration, dyspnoea and hypoxia) have been reported (see Precautions).
Exacerbation of arthritic symptoms has been uncommonly observed.
Leukocytosis (WBC > 50 x 109/l) was observed in 41% of donors and transient thrombocytopenia (platelets < 100 x 109/l) following filgrastim and leukapheresis was observed in 35% of donors (see Precautions).
In SCN patients: Undesirable effects seen include splenomegaly, which may be progressive in a minority of cases, splenic rupture and thrombocytopenia (see Precautions).
Undesirable effects possibly related to Neupogen therapy and typically occurring in < 2% of SCN patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis, and rash.
During long-term use cutaneous vasculitis has been reported in 2% of SCN patients.
In patients with HIV: Splenomegaly was reported to be related to Neupogen therapy in < 3% of patients. In all cases this was mild or moderate on physical examination and the clinical course was benign; no patients had a diagnosis of hyperplenism and no patients underwent splenectomy. As splenomegaly is a common finding in patients with HIV infection and is present to varying degrees in most patients with AIDS, the relationship to Neupogen treatment is unclear (see Precautions).
Paediatric population: Data from clinical studies in paediatric patients indicate that the safety and efficacy of Neupogen are similar in both adults and children receiving cytotoxic chemotherapy suggesting no age-related differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.
There is insufficient data to further evaluate Neupogen use in paediatric subjects.
Other special populations: Geriatric use: No overall differences in safety or effectiveness were observed between subjects over 65 years of age compared to younger adult (> 18 years of age) subjects receiving cytotoxic chemotherapy and clinical experience has not identified differences in the responses between elderly and younger adult patients. There is insufficient data to evaluate Neupogen use in geriatric subjects for other approved Neupogen indications.
Paediatric SCN patients: Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe chronic neutropenia receiving chronic treatment with Neupogen. The frequency is estimated as 'common' from clinical trial data.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions as per local regulations.
Drug Interactions
The safety and efficacy of Neupogen 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 Neupogen 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 Neupogen 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, lithium is likely to potentiate the effect of Neupogen. Although this interaction has not been formally investigated, there is no evidence that such an interaction is harmful.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Avoid vigorous shaking.
The solution should be visually inspected prior to use. Only clear solutions without particles should be used.
Filgrastim vials and syringes are for single use only.
Instructions for dilution: If required, filgrastim may be diluted in 5% glucose. Dilution to a final concentration less than 5 mcg/per ml is not recommended at any time.
For patients treated with Neupogen 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 20% human albumin solution Ph. Eur. added.
Diluted Neupogen solutions should not be prepared more than 24 hours before administration and should also be stored refrigerated at 2 - 8ºC.
Disposal of Unused/Expired Medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the patient's location.
Incompatibilities: Neupogen should not be diluted with saline solutions. If required, Neupogen may be diluted in 5% glucose.
Diluted Neupogen may be adsorbed to glass and plastic materials. However, when diluted in 5% glucose solution, Neupogen is compatible with glass and a variety of plastic including PCV, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.
Neupogen vials and pre-filled syringes are for single-dose only.
Storage
Neupogen should be stored in a refrigerator at 2 - 8ºC. Accidental exposure to freezing temperatures does not adversely affect the stability of Neupogen.
For storage of diluted solutions see Special Instructions for Use, Handling and Disposal under Caution for Usage.
ATC Classification
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Presentation/Packing
Soln for inj 30 MU/0.5 mL (pre-filled syringe) x 1's.
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