Zarzio

Zarzio

filgrastim

Manufacturer:

Sandoz

Distributor:

Zuellig
/
Firma Vai Hong
Full Prescribing Info
Contents
Filgrastim.
Description
Each mL of solution contains  filgrastim* 60 million units (MU) (equivalent to 600 mcg). Each pre-filled syringe contains filgrastim 30 MU (equivalent to 300 mcg) in 0.5 mL. Each mL of solution contains the following excipients: Glutamic acid, sorbitol (E420) 50 mg, polysorbate 80, water for injection.
*Recombinant methionylated human granuloycte-colony stimulating factor (G-CSF) produced in Escherichia coli by recombinant DNA technology.
Action
Pharmacotherapeutic Group: Immunostimulants, colony-stimulating factors. ATC Code: L03AA02.
Pharmacology: Pharmacodynamics: Zarzio is a biosimilar medicinal product.
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Zarzio containing r-metHuG-CSF (filgrastim) causes marked increase in peripheral blood neutrophil counts within 24 hrs, with minor increases in monocytes. In some severe chronic neutropenia (SCN) patients, filgrastim 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 in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within 1-2 days and to normal levels within 1-7 days.
Use of Filgrastim in Patients Undergoing Cytototxic Chemotherapy: Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalization after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. The incidence of fever and documented infections were not reduced in either setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
Use of Filgrastim (Either Alone or After Chemotherapy): Use of filgrastim either alone or after chemotherapy, mobilizes hematopoietic progenitor cells into the peripheral blood. These autologous peripheral blood progenitor cells (PBPCs) may be harvested and infused after high dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs accelerates hematopoietic recovery reducing the duration of risk for hemorrhagic complications and the need for platelet transfusions.
Recipients of allogenic PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogenic bone marrow transplantation.
One (1) retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukaemias suggested an increase in the risk of graft versus host disease (GvHD), treatment-related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the results of 9 prospective randomized trials, 8 retrospective studies and 1 case-controlled study, did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related mortality. (See Table 1.)

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Use of Filgrastim for the Mobilisation of PBPCs in Normal Donors Prior to Allogeneic PBPC Transplantation: In normal donors, a 1 MU/kg/day (10 mcg/kg/day) dose administered SC for 4-5 consecutive days allows a collection of ≥4 x 106 CD34+ cells/kg recipient body weight in the majority of the donors after 2 leukapheresis.
Use of Filgrastim in Children or Adults with SCN: Use of filgrastim in children or adults with SCN (severe congenital, cyclic and idiopathic neutropenia) induces a sustained increase in anthocyanins (ACNs) in peripheral blood and a reduction of infection and related events.
Use of Filgrastim in Patients with HIV Infection: Use of filgrastim in patients with human immunodeficiency virus (HIV) infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive treatments. There is no evidence that patients with HIV-infection treated with filgrastim 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: Randomised, double-blind, single and multiple dose, crossover studies in 204 healthy volunteers showed that the pharmacokinetic profile of Zarzio was comparable to that of the reference product after SC and IV administration.
Absorption: A single SC dose of 0.5 MU/kg (5 mcg/kg) resulted in maximum serum concentrations after a time peak plasma (tmax) of 4.5 ± 0.9 hrs (mean ± SD).
Distribution: The volume of distribution in blood is approximately 150 mL/kg. Following SC administration of recommended doses, serum concentrations were maintained above 10 ng/mL for 8-16 hrs. There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered IV or SC.
Elimination: The median serum elimination half-life (t½) of filgrastim after single SC doses ranged from 2.7 hrs (1 MU/kg, 10 mcg/kg) to 5.7 hrs (0.25 MU/kg, 2.5 mcg/kg) and was prolonged after 7 days of dosing to 8.5-14 hrs, respectively. Continuous infusion with filgrastim 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.
Indications/Uses
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 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.
Mobilization of peripheral blood progenitor cells (PBPC).
In children and 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 filgrastim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Treatment of persistent neutropenia (ANC ≤1 x 109/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other therapeutic options are inappropriate.
Dosage/Direction for Use
Filgrastim therapy should only be given in collaboration with an oncology center which has experience in granulocyte-colony stimulating factor (G-CSF) treatment and hematology and has the necessary diagnostic facilities.
The mobilization and apheresis procedures should be performed in collaboration with an oncology-hematology center with acceptable experience in this field and where the monitoring of hematopoietic progenitor cells can be correctly performed.
Established Cytotoxic Chemotherapy: Recommended Dose: 0.5 MU/kg/day (5 mcg/kg/day). The 1st dose of filgrastim should not be administered <24 hrs following cytotoxic chemotherapy.
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 leukemias, 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 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 count 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.
Patients Treated with Myeloablative Therapy Followed by Bone Marrow Transplantation: Recommended Starting Dose: 1 MU/kg/day (10 mcg/kg/day). The 1st dose of filgrastim should not be administered <24 hrs following cytotoxic chemotherapy and within 24 hrs of bone marrow infusion.
Dose Adjustments: Once the neutrophil nadir has been passed, the daily dose of filgrastim should be titrated against the neutrophil response as follows: See Table 2.

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Mobilisation of Peripheral Blood Progenitor Cell (PBPC):
 Patients Undergoing Myelosuppressive or Myeloablative Therapy Followed by Autologous PBPC Transplantation: Recommended Dose: 1 MU/kg/day (10 mcg/kg/day) for 5-7 consecutive days when used alone. 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.
PBPC Mobilization After Myelosuppressive Chemotherapy: Recommended dose: 0.5 MU/kg/day (5 mcg/kg/day) given daily from the 1st 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 x 109/L. For patients who have not had extensive chemotherapy, 1 leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended.
Normal Donors Prior to Allogeneic PBPC Transplantation: For PBPC mobilization in normal donors, filgrastim should be adiministered at 1 MU/kg/day (10 mcg/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 106 CD34+ cells/kg recipient body weight.
Severe Chronic Neutropenia (SCN): Congenital Neutropenia: Recommended Starting Dose: 1.2 MU/kg/day (12 mcg/kg/day) as a single dose or in divided doses.
Idiopathic or Cyclic Neutropenia: Recommended Starting Dose: 0.5 MU/kg/day (5 mcg/kg/day) as a single dose or in divided doses.
Dose Adjustments: Filgrastim should be administered daily until the neutrophil count has reached and can be maintained at >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 1-2 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 ≤2.4 MU/kg/day (24 mcg/kg/day). The long-term safety of filgrastim administration above 2.4 MU/kg/day (24 mcg/kg/day) in patients with SCN has not been established.
HIV Infection: Reversal of Neutropenia: Recommended Starting Dose: 0.1 MU/kg/day (1 mcg/kg/day) given daily with titration up to a maximum of 0.4 MU/kg/day (4 mcg/kg/day) until a normal neutrophil count is reached and can be maintained (ANC >2 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 MU/kg/day (10 mcg/kg/day) were required to achieve reversal of neutropenia.
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/day (300 mcg/day) is recommended. Further dose adjustment may be necessary, as determined by the patient's ANC, to maintain the neutrophil count at >2 x 109/L. In clinical studies, dosing with 30 MU/day (300 mcg/day) on 1-7 days per week was required to maintain the ANC >2 x 109/L, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC >2 x 109/L.
Special Populations: Renal/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.
Paediatric Patients in the SCN and Cancer Settings: Sixty-five percent (65%) of the patients studied in the SCN trial were under <18 years. 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 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.
Elderly: 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.
Administration: Established Cytotoxic Chemotherapy: Filgrastim may be given as a daily SC injection or as a daily IV infusion, diluted in glucose 5% solution over 30 min. The SC route is preferred in most cases. There is some evidence from a study of single dose administration that IV 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 randomised clinical studies, a SC dose of 23 MU/m2/day (230 mcg/m2/day) was used.
Patients Treated with Myeloablative Therapy Followed by Bone Marrow transplant: Filgrastim is administered as an IV short-term infusion over 30 min or as a SC or IV continuous infusion over 24 hrs. Filgrastim should be diluted in 20 mL of glucose 5% solution.
Mobilisation of PBPC: For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation, the recommended dose of filgrastim may also be administered as a 24-hr SC continuous infusion or a single daily SC injection for 5-7 days. For infusions, filgrastim should be diluted in 20 mL of glucose 5% solution.
SCN/HIV infection: SC injection.
For instructions on dilution of Zarzio before administration, see Cautions for Usage.
Overdosage
The effects of filgrastim overdosage have not been established. Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1-2 days, with a return to normal levels in 1-7 days.
Contraindications
Hypersensitivity to filgrastim or to any of the excipients of Zarzio.
Warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosing regimens (see as follows).
Filgrastim should not be administered to patients with severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution.
Special Precautions
Established Cytotoxic Chemotherapy: Malignant Cell Growth: G-CSF 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 filgrastim administration in patients with myelodysplastic syndrome or chronic myelogenous leukaemia have not been established. Filgrastim is not indicated for use in these conditions. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
In view of limited safety and efficacy data in patients with secondary acute myeloid leukaemia (AML), filgrastim should be administered with caution.
The safety and efficacy of filgrastim administration in de novo AML patients aged <55 years with good cytogenetics [t(8;21), t(15;17) and inv(16)] have not been established.
Leucocytosis: White blood cell counts of ≥100 x 109/L have been observed in <5% of patients receiving filgrastim at doses above 0.3 MU/kg/day (3 mcg/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 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, it should be discontinued or its dose 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.
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy (eg, 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-mobilized 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 (eg, 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 Pharmacology: Pharmacodynamics under Actions).
Increased haematopoietic activity of the bone marrow in response to growth factor has been associated with transient abnormal bone scans. This should be considered when interpreting bone-imaging results.
Mobilisation of PBPC: There are no prospectively randomised comparisons of the 2 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 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, followed by administration of filgrastim for mobilisation of PBPCs may not show sufficient mobilisation of these blood cells to achieve the recommended minimum yield (≥2 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 eg, 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 filgrastim 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 mentioned, 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 reinfused and the rate of platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. The recommendation of a minimum yield of ≥2 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.
Normal Donors Prior to Allogeneic PBPC Transplantation: 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 filgrastim have not been assessed in normal donors <16 years or >60 years.
Transient thrombocytopenia (platelets <100 x 109/L) following filgrastim administration and leukapheresis was observed in 35% of subjects studied. Among these, 2 cases of platelets <50 x 109/L were reported and attributed to the leukapheresis procedure. If >1 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 haemostasis.
Filgrastim administration should be discontinued or its dose should be reduced if the leukocyte counts rise to >70 x 109/L.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices return to normal.
Transient cytogenetic modifications 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 can not be excluded. It is recommended that the apheresis center 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 very rare cases of splenic rupture have been reported in healthy donors and patients following administration of G-CSFs. Some cases of splenic rupture were fatal. Therefore, spleen size should be carefully monitored (eg, 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 filgrastim should be considered and appropriate medical care given.
Recipients of Allogeneic PBPCs 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.
Severe Congenital Neutropenia (SCN): Blood Cell Counts: 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 ie, 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 eg, 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 study patients with SCN-treated with filgrastim. This observation has only been made in patients with congenital neutropenia. Myelodysplastic syndrome and leukaemias are natural complications of the disease and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including monosomy 7, on routine repeat evaluation. It is currently unclear whether long-term treatment of patients with SCN will predispose patients to cytogenetic abnormalities, MDS or 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 eg, viral infections should be excluded.
Splenomegaly is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of patients in studies were documented as having palpable splenomegaly. Increases in volume, measured radiographically, occurred early during filgrastim 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 urine analyses should be performed to monitor this event.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
Human Immunodeficiency Virus (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 2 weeks and subsequently once per week or once every other week during maintenance therapy. During intermittent dosing with 30 MU/day (300 mcg/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 Drugs: Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive treatments. As a result of the potential to receive higher doses or a greater number of these drugs 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 eg, Mycobacterium avium complex or malignancies eg, 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.
Other Special Precautions: Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration (see Adverse Reactions). Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs eg, cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment given in these cases.
Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with filgrastim for >6 months.
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in patients with sickle cell disease and only after careful evaluation of the potential risks and benefits.
Capillary leak syndrome (CLS) has been reported after the administration of filgrastim or pegfilgrastim. CLS can cause circulatory shock and may be fatal, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive treatment, which may include a need for intensive care.
Excipients: Zarzio contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use Zarzio.
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.
Effects on the Ability to Drive or Operate Machinery: Filgrastim has no or negligible influence on the ability to drive and use machines.
Use in pregnancy: There are no or limited amount of data from the use of filgrastim in pregnant women. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. There is no evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of embryo loss has been observed in rabbits, but no malformation has been seen.
In pregnancy, the possible risk of filgrastim use to the foetus must be weighed against the expected therapeutic benefit.
Use in lactation: It is unknown whether filgrastim or its metabolites are excreted in human milk, therefore it is not recommended for use in breastfeeding women.
Use In Pregnancy & Lactation
Use in pregnancy: There are no or limited amount of data from the use of filgrastim in pregnant women. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. There is no evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of embryo loss has been observed in rabbits, but no malformation has been seen.
In pregnancy, the possible risk of filgrastim use to the foetus must be weighed against the expected therapeutic benefit.
Use in lactation: It is unknown whether filgrastim or its metabolites are excreted in human milk, therefore it is not recommended for use in breastfeeding women.
Adverse Reactions
Summary of the Safety Profile: In clinical trials in cancer patients, the most frequent undesirable effects were musculoskeletal pain which was mild or moderate in 10%, and severe in 3% of patients.
Graft versus Host Disease (GvHD) has also been reported.
In PBPC mobilisation in normal donors, the most commonly reported undesirable effect was musculosceletal pain. Leucocytosis 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 filgrastim were bone pain, general musculoskeletal pain and splenomegaly. Myelodysplastic syndromes (MDS) or leukaemia have developed in patients with congenital neutropaenia treated with filgrastim (see Precautions).
Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported uncommonly (≥1/1000 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).
In clinical studies in patients with HIV, the only undesirable effects that were consistently considered to be related to filgrastim administration were musculoskeletal pain, bone pain and myalgia.
Tabulated summary of Adverse Reactions: The data in the tables describe adverse reactions reported form clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects reported are presented in order of decreasing seriousness. Data are presented separately for cancer patients, PBPC mobilisation in normal donors, SCN patients and patients with HIV, reflecting the different adverse reaction profiles in these populations. (See Tables 3-6.)

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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 Pharmacology under Actions and 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, filgrastim 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 filgrastim/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), constipation and pain.
In the post-marketing setting, cutaneous vasculitis has been reported in patients treated with filgrastim. The frequency is estimated as uncommon from clinical trial data. Cases of Sweets syndrome (acute febrile dermatosis) have 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).
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and post-marketing experience. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim 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 disease (see Precautions). The frequency is estimated as uncommon from clinical trial data.
Pseudogout has been reported in patients with cancer treated with filgrastim. 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 G-CSFs (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.
In SCN Patients: Undesirable effects seen include splenomegaly, which may be progressive in a minority of cases and thrombocytopenia. Undesirable effects possibly related to filgrastim 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 filgrastim 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 filgrastim treatment is unclear.
Paediatric population. 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 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 filgrastim use in paediatric subjects.
Paediatric SCN Patients: Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe chronic neutropenia receiving chronic treatment with filgrastim. The frequency is estimated as 'common' from clinical trial data.
Geriatric Use: No overall differences in safety or effectiveness were observed between subjects >65 years compared to younger adult (>18 years) 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 filgrastim use in geriatric subjects for other approved filgrastim indications.
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 Zarzio. Healthcare professionals are asked to report any suspected adverse reactions.
Drug Interactions
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 hrs before to 24 hrs 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 hematopoietic growth factors and cytokines have not yet been investigated in clinical studies.
Since lithium promotes the release of neutrophils, lithium 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.
Incompatibilities: Zarzio must not be diluted with sodium chloride solutions.
Zarzio must not be mixed with other drugs except those mentioned in Cautions for Usage.
Diluted filgrastim may be adsorbed to glass and plastic materials, unless it is diluted in glucose 50 mg/mL (5%) solution.
Caution For Usage
Instructions for Use, Handling and Disposal: The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Accidental exposure to freezing temperatures does not adversely affect the stability of filgrastim.
Zarzio contains no preservative: In view of the possible risk of microbial contamination, Zarzio syringes are for single use only.
Dilution Prior to Administration (Optional): If required, Zarzio may be diluted in glucose 50 mg/mL (5%) solution. Dilution to a final concentration <0.2 MU/mL (2 mcg/mL) is not recommended at any time.
For patients treated with filgrastim diluted to concentrations <1.5 MU/mL (15 mcg/mL), human serum albumin (HSA) should be added to a final concentration of 2 mg/mL.
When diltued in glucose 50 mg/mL (5%) solution, filgrastim is compatible with glass and a variety of plastic including polyvinylchloride, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
Using the Pre-Filled Syringe With a Needle Safety Guard: The needle safety guard covers the needle after injection to prevent needle stick injury. This does not affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. While maintaining pressure on the plunger, remove the syringe from the patient. The needle safety guard will cover the needle when releasing the plunger.
Using the Pre-Filled Syringe Without a Needle Safety Guard: Administer the dose as per standard protocol.
Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store in a refrigerator (2-8°C).
Keep the pre-filled syringe in the outer carton to protect from light.
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 1 single period of up to 72 hrs. At the end of this period, the product should not be put back in the refrigerator and should be disposed of.
Shelf-Life: 36 months.
After Dilution: Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hrs at 2°-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hrs at 2°-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
ATC Classification
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Presentation/Packing
Soln for inj or infusion (pre-filled syringe, clear, colorless to slightly yellowish soln) 30 MU/0.5 mL x 5's.
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