NEUPOGEN

Neupogen therapy should only be given in collaboration with an oncology centre 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 centre with acceptable experience in this field and where the monitoring of haematopoietic progenitor cells can be correctly performed.

5 MU (5 μg)/kg/day. The first dose of Neupogen should be administered at least 24 hours after cytotoxic chemotherapy. 4 μg/kg/day) was used. 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 tumours, lymphomas, and lymphoid leukaemia, 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 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. 6). 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. 0 MU (10 μg)/kg/day. The first dose of Neupogen should be administered at least 24 hours following cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.

0 × 109/l during the treatment period the dose of Neupogen should be re-escalated according to the above steps ANC = absolute neutrophil count Method of administration Neupogen may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 24 hour subcutaneous infusion.

6). 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. Neupogen dosing should be maintained until the last leukapheresis.

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. 0 × 109/l. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient.

In other circumstances, additional leukapheresis are recommended.

Method of administration Neupogen for PBPC mobilisation when used alone:

Neupogen may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. 6).

Neupogen for PBPC mobilisation after myelosuppressive chemotherapy:

Neupogen should be given by subcutaneous injection. 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 × 106 CD34+ cells/kg recipient bodyweight.

Method of administration Neupogen should be given by subcutaneous injection. 2 MU (12 μg)/kg/day, as a single dose or in divided doses. 5 MU (5 μg)/kg/day, as a single dose or in divided doses. 5 × 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 […]

8. Special warnings and precautions associated with co-morbidities Special precautions in sickle cell trait and sickle cell disease Sickle cell crises, in some cases fatal, have been reported with the use of 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 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 Neupogen alone does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. 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 Neupogen mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.

Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients In the post-marketing observational study setting, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (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 tumour).

Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported occasionally in patients undergoing high-dose chemotherapy followed by transplantation. 1). 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.

0 ×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 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 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. 0 × 106 CD34+ cells/kg is based on published […]

Special warnings 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 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. Glomerulonephritis Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim.

Urinalysis monitoring is recommended. Capillary leak syndrome Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported after granulocyte-colony stimulating factor administration, and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration.

8). Splenomegaly and splenic rupture Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported in patients and normal donors following administration of Neupogen. Some cases of splenic rupture were fatal.

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 Neupogen have been noted to slow or stop the progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a splenectomy was required.

Malignant cell growth Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. Myelodysplastic syndrome or chronic myeloid leukaemia The safety and efficacy of Neupogen administration in patients with myelodysplastic syndrome, or chronic myelogenous leukaemia 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 leukaemia from acute myeloid leukaemia. Acute myeloid leukaemia 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. Thrombocytopenia Thrombocytopenia has been reported in patients receiving Neupogen.

Platelet counts should be monitored closely, especially during the first few weeks of Neupogen therapy. Consideration should be given to temporary discontinuation or dose reduction of Neupogen in patients with severe chronic neutropenia who develop thrombocytopenia (platelet count < 100 × 109/l).

3 MU/kg/day (3 μg/kg/day). No undesirable effects directly attributable to this degree of leucocytosis have been reported. However, in view of the potential risks associated with severe leucocytosis, a white blood cell count should be performed at regular intervals during Neupogen therapy.

If leucocyte counts exceed 50 × 109/l after the expected nadir, Neupogen should be discontinued immediately. When administered for PBPC mobilisation, Neupogen should be discontinued or its dosage should be reduced if the leucocyte 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 neutralising activity at present.

Aortitis Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. 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.

8. Special warnings and precautions associated with co-morbidities Special precautions in sickle cell trait and sickle cell disease Sickle cell crises, in some cases fatal, have been reported with the use of 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 tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead to increased […]

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