Neupogen 30 MU vials & 30 MU, 48 MU Pre-filled Syringe

/ Amgen

Established cytotoxic chemotherapy:
Posology: The recommended dose of Filgrastim is 0.5 MU (5 µg)/kg/day. The first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy. In randomized clinical trials, a subcutaneous dose of 230 µg/m²/day (4.0 to 8.4 µg/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 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 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.
Method of administration: Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 5% glucose solution given over 30 minutes. 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.
In patients treated with myeloablative therapy followed by bone marrow transplantation: 
Posology: The recommended starting dose of Filgrastimis 1.0 MU (10 µg)/kg/day. The first dose of this medicinal product should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Once the neutrophil nadir has been passed, the daily dose of Filgrastim should be titrated against the neutrophil response as follows:
Neutrophil Count> 1.0 x 10^9/l for 3 consecutive days: Reduce to 0.5 MU (5 µg)/kg/day.
Then, if ANC* remains > 1.0 x 10^9 /l for 3 more consecutive days: Discontinue Filgrastim.
If the ANC* decreases to < 1.0 x 10^9/l during the treatment period the dose of Filgrastim should be re-escalated according to the above steps.
*ANC = absolute neutrophil count
Method of administration: Filgrastim may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 24 hour subcutaneous infusion. Filgrastim should be diluted in 20 ml of 5% glucose solution.
For the mobilization of PBPCs in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation: 
Posology: The recommended dose of Filgrastim for PBPC mobilization when used alone is 1.0 MU (10 µg)/kg/day for 5 to 7 consecutive days. Timing of leukapheresis: one or two leukapheresis on days 5 and 6 are often sufficient. In other circumstances, additional leukapheresis may be necessary. Filgrastim dosing should be maintained until the last leukapheresis.
The recommended dose of Filgrastim for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU (5 µg)/kg/day 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 10^9/l to > 5.0 x 10^9/l. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional leukapheresis are recommended.
Method of administration: Filgrastim for PBPC mobilization 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 mobilization after myelosuppressive chemotherapy:
Filgrastim should be given by subcutaneous injection.
For the mobilization of PBPCs in normal donors prior to allogeneic PBPC transplantation:
Posology: For PBPC mobilization in normal donors, Filgrastim should be administered at 1.0 MU (10 µg)/kg/day 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 10^6 CD34+cells/kg recipient body weight.
Method of administration: Filgrastim should be given by subcutaneous injection.
In patients with severe chronic neutropenia (SCN):
Posology: 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 adjustment: Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 x 10^9/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 10^9/l and 10 x 10^9/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 Filgrastim administration above 24 µg/kg/day in patients with SCN has not been established.
Method of administration: Congenital, idiopathic or cyclic neutropenia: Filgrastim should be given by subcutaneous injection.
In patients with HIV infection
Posology: For reversal of neutropenia: The recommended starting dose of Filgrastim is 0.1 MU (1 μg)/kg/day, 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 × 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 is recommended. Further dose adjustment may be necessary, as determined by the patient’s ANC, to maintain the neutrophil count at > 2.0 × 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 × 10⁹/l, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC > 2.0 × 10⁹/l.
Method of administration: Reversal of neutropenia or maintaining normal neutrophil counts: Filgrastim should be given by subcutaneous injection
Older people: 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 dosage 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.
Pediatric use in the SCN and cancer settings: Sixty-five percent of the 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 pediatric patients treated for SCN.
Data from clinical studies in pediatric patients indicate that the safety and efficacy of Filgrastim are similar in both adults and children receiving cytotoxic chemotherapy.
The dosage recommendations in pediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy.

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 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 Filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Filgrastim is indicated for the mobilization 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 × 109/l, and a history of severe or recurrent infections, long-term administration of Filgrastim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Filgrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 × 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.

Special warning and precautions across indications
Hypersensitivity: 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.
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). Neupogen should be discontinued and appropriate treatment given.
Glomerulonephritis: Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Capillary leak syndrome : Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported after granulocyte-colony stimulating factor administration, and is characterized by hypotension, hypoalbuminemia, 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.
Splenomegaly and splenic rupture: Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported in patients and normal donors following administration.  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.  This medicinal product 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  administration in de novo AML patients aged < 55 years with good cytogenetics (t(8;21), t(15;17), and in v(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 therapy.  Consideration should be given to temporary discontinuation or dose reduction in patients with severe chronic neutropenia who develop thrombocytopenia (platelet count < 100 × 109/l).
Leukocytosis: White blood cell counts of 100 × 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 therapy.  If leukocyte counts exceed 50 × 109/l after the expected nadir,  should be discontinued immediately.  When administered for PBPC mobilization, drug should be discontinued or its dosage should be reduced if the leukocyte counts rise to > 70 × 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.
Special warnings and precautions associated with co-morbidities
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.
Osteoporosis: 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.
Special precautions in cancer patients
Neupogen 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 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 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 Neupogen 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 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 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 GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation.
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 randomized comparisons of the two recommended mobilization methods (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 10^6 CD34+ cells/kg) or acceleration of platelet recovery, to the same degree.
Special precautions in normal donors undergoing PBPC 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 hematological values and infectious disease.
The safety and efficacy of filgrastim have not been assessed in normal donors < 16 years or > 60 years.
Transient thrombocytopenia (platelets < 100 × 10⁹/l) following filgrastim administration and leukapheresis was observed in 35% of subjects studied.  Among these, two cases of platelets < 50 × 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 × 10⁹/l prior to leukapheresis; in general apheresis should not be performed if platelets < 75 × 10⁹/l.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in hemostasis.
Donors who receive G‑CSFs for PBPC mobilization should be monitored until hematological indices return to normal.
Special precautions in recipients of allogeneic PBPCs mobilized 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
Neupogen should not be administered to patients with severe congenital neutropenia who develop leukemia or have evidence of leukemic evolution.
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 these events.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
See prescribing information for full details.
Special precautions in patients with HIV infection
Blood cell counts: Absolute neutrophil count (ANC) should be monitored closely, especially during the first few weeks of Filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil count to the initial dose of Filgrastim. It is recommended that the ANC is measured daily for the first 2-3 days of Filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice per week for the first two weeks and subsequently once per week or once every other week during maintenance therapy. During intermittent dosing with 30 MU (300 μg)/day of Filgrastim, there can be wide fluctuations in the patient’s ANC over time. In order to determine a patient’s trough or nadir ANC, it is recommended that blood samples are taken for ANC measurement immediately prior to any scheduled dosing with Filgrastim.
Risk associated with increased doses of myelosuppressive medications:
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.
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.

The most serious adverse reactions that may occur during treatment include: anaphylactic reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.
The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain), anemia, vomiting, and nausea. In clinical trials in cancer patients musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients.
See prescribing information for full details.

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 hematopoietic 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.

Pregnancy: There are no or limited amount of data from the use of filgrastim in pregnant women. Neupogen is not recommended during pregnancy.
Breast-feeding: 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 breast-feeding or to discontinue/abstain from Neupogen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
See prescribing information for full details.

The effects of Neupogen overdosage have not been established. Discontinuation of Neupogen 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.

Incompatibilities: Neupogen should not be diluted with saline solutions.
Diluted filgrastim may be adsorbed to glass and plastic materials. 
Storage: Store at 2°C to 8°C.
Shelf life: 30 months.
See prescribing information for full details.