Alvograstim

Alvograstim

filgrastim

Manufacturer:

MR Pharma

Distributor:

Maxxcare

Marketer:

Mega Lifesciences
Full Prescribing Info
Contents
Filgrastim.
Description
Each pre-filled syringe contains 30 million units (300 micrograms (µg)) of filgrastim in 1 ml (0.3 mg/ml).
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced by r-DNA technology in E. coli.
Excipients/Inactive Ingredients: Sodium acetate trihydrate, acetic acid, sorbitol, polysorbate 80, water for injection.
Action
Pharmacotherapeutic Group: Cytokines. ATC Code: L03AA02.
Pharmacology: Pharmacodynamics: Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Alvograstim containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within twenty-four hours, with minor increases in monocytes. In some 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 to 2 days and to normal levels within 1 to 7 days.
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 hospitalisation 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, mobilises haematopoietic progenitor cells into the peripheral blood. These autologous PBCPs 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 PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.
One 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 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 nine 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 10 µg/kg/day dose administered subcutaneously for 4 to 5 consecutive days allows a collection of ≥4 x 106 CD34+ cells/kg recipient body weight in the majority of the donors after 2 leukaphereses.
Use of filgrastim in patients, children or adults, with SCN (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 filgrastim 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 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: Distribution: The volume of distribution in blood is approximately 150 ml/kg.
Elimination: Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The serum elimination half-life of filgrastim is approximately 3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. 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.
Linearity/non-linearity: There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 mg/ml for 8 to 16 hrs.
Toxicology: Preclinical safety data: There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the monograph.
Indications/Uses
Alvograstim 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 leukaemia and myelodysplastic syndromes).
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.
Mobilisation of peripheral blood progenitor cells (PBPCs).
Increase in neutrophil counts and reduction in the incidence and duration of infection-related events after long term administration in patients, children or adults, with severe congenital, cyclic or idiopathic neutropenia with an ANC of ≤0.5 x 109/L, and a history of severe or recurrent infections.
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
Established cytotoxic chemotherapy: The recommended daily dose of Alvograstim is 0.5 MIU (5 µg)/kg. The first dose of Alvograstim should not be administered less than 24 hours following cytotoxic chemotherapy.
This medicine may be given as a daily subcutaneous injection. Daily dosing with Alvograstim 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 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 counts is typically seen 1 to 2 days after initiation of therapy. However, for a sustained therapeutic response, Alvograstim therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of therapy, prior to the time of the expected neutrophil nadir, is not recommended.
In patients treated with myeloablative therapy followed by bone marrow transplantation: The recommended starting daily dose of Alvograstim is 1.0 MIU (10 µg)/kg given as a 30 minute or 24 hour intravenous infusion or 1.0 MIU (10 µg)/kg given by continuous 24 hour subcutaneous infusion.
Alvograstim should be diluted in 20 ml of 5% glucose solution (see Cautions for Usage).
The first dose should not be administered less than 24 hours following cytotoxic chemotherapy and within 24 hours of bone marrow infusion.
Once the neutrophil nadir has been passed, the daily dose should be titrated against the neutrophil response as shown in Table 2.

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For the mobilisation of PBPCs in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation: The recommended daily dose for PBPC mobilisation when used alone is 1.0 MU (10 µg)/kg as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection for 5 to 7 consecutive days.
For infusions, Alvograstim should be diluted in 20 ml of 5% glucose solution (see Cautions for Usage). Timing of leukapheresis: one or two leukapheresis on days 5 and 6 are often sufficient. In other circumstances, additional leukapheresis may be necessary. Alvograstim dosing should be maintained until the last leukapheresis.
The recommended daily dose for PBPC mobilisation after myelosuppressive chemotherapy is 0.5 MIU (5 µg)/kg given 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 leukapheresis are recommended.
For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation: For PBPC mobilisation in normal donors, Alvograstim 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 recipient bodyweight.
In patients with severe chronic neutropenia (SCN): Congenital neutropenia: The recommended daily starting dose is 1.2 MIU (12 μg)/kg subcutaneously as a single dose or in divided doses.
Idiopathic or cyclic neutropenia: The recommended daily starting dose is 0.5 MIU (5 µg)/kg subcutaneously as a single dose or in divided doses.
Dose adjustments: Chronic daily administration is required to maintain clinical benefit.
Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patients' clinical course as well as ANC.
In the SCN post-marketing surveillance study, the reported median daily doses of Alvograstim were: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia) and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Alvograstim ≥100 mcg/kg/day.
Dilution: If required, Alvograstim may be diluted in 5% dextrose. The medicine diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL.
When diluted in 5% glucose or 5% glucose plus Albumin (Human), Alvograstim is compatible with glass bottles, PVC and polyolefin IV bags, and polypropylene syringes.
Dilution of the medicine to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate.
Other particulars: Alvograstim 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.
In patients with HIV infection: For reversal of neutropenia: The recommended daily starting dose is 0.1 MIU (1 µg)/kg given daily by subcutaneous injection with titration up to a maximum of 0.4 MU (4 µg)/kg 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 daily 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 MIU (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 MIU (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.
Overdosage
The effects of filgrastim overdose have not been established. Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels in 1 to 7 days.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Excipients/Inactive Ingredients under Description.
Special Precautions
The medicine should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
The medicine should not be administered to patients with severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution.
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 filgrastim administration in patients with myelodysplastic syndrome, or chronic myelogenous leukaemia have not been established.
The medicine 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 AML, Alvograstim 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.
Other special precautions: Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with Alvograstim for more than 6 months.
Pulmonary adverse effects, in particular interstitial pneumonia, 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). Alvograstim should be discontinued and appropriate treatment given.
Special precautions in cancer patients: 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 increased toxicities including cardiac, pulmonary, neurologic, and dermatologic effects (please refer to the prescribing information of the specific chemotherapy agents used).
Treatment with Alvograstim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy (e.g., full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
The use of Alvograstim-mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions: The effects of Alvograstim in patients with substantially reduced myeloid progenitors have not been studied. Alvograstim 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).
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient abnormal bone scans. This should be considered when interpreting bone-imaging results.
Special precautions in patients undergoing PBPC mobilisation: Mobilisation: There are no prospectively randomised comparisons of the two recommended mobilisation methods (Alvograstim 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 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 above, alternative forms of treatment, not requiring progenitor support should be considered.
Assessment of progenitor cell yields: In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular attention should be paid to the method of quantitation. The results of flow cytometric analysis of CD34+ cell numbers vary depending on the precise methodology used and 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 ≥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 below 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 allogenic 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, 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 haemostasis.
Filgrastim 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 mobilisation should be monitored until haematological indices return to normal.
Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The significance of these changes is unknown.
Long-term safety follow-up of donors is ongoing. Nevertheless, a risk of promotion of a malignant myeloid clone can not 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 very rare 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, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, dyspnoea and hypoxia) have been reported very rarely in post marketing experience. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should be considered and appropriate medical care given.
Special precaution in recipients of allogenic PBPCs mobilised with Alvograstim: 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: Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in patients who develop thrombocytopenia, i.e. platelets consistently <100,000/mm3.
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, which require close monitoring of cell counts.
Transformation to leukaemia or myelodysplastic syndrome: Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic disorders such as aplastic anaemia, myelodysplasia, and myeloid leukaemia. Complete blood cell counts with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype should be performed prior to treatment.
Other special precautions: Causes of transient neutropenia, such as viral infections should be excluded.
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/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: 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 anaemia 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 anaemia. Regular monitoring of blood counts is recommended (see previous discussions).
Infections and malignancies causing myelosuppression: Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. In patients with known bone marrow infiltrating infections or malignancy, consider appropriate therapy for treatment of the underlying condition, in addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on neutropenia due to bone marrow infiltrating infection or malignancy have not been well established.
Special precautions in sickle cell disease: Sickle cell 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.
Alvograstim contains Sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Alvograstim contains less than 1 mmol (23 mg) Sodium per 0.3 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.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use In Pregnancy & Lactation
Pregnancy: The safety of filgrastim 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. There is no evidence from studies in rats and rabbits that filgrastim is teratogenic. In pregnancy, the possible risk of filgrastim use to the foetus must be weighed against the expected therapeutic benefit.
Breastfeeding: It is not known whether filgrastim is excreted in human milk. Filgrastim is not recommended for use in nursing women.
Fertility: An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been seen.
Adverse Reactions
Clinical Trial Experience: All adverse effects are grouped according to the order based on the MedDRA System Organ Classes (SOC). Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.
Assessment of Adverse Effects is based on the following frequency groupings: Very common: ≥1/10; Common: ≥1/100, <1/10; Uncommon: ≥1/1,000, <1/100; Rare: ≥1/10,000, <1/1,000; Very rare: <1/10,000; Not known: cannot be estimated from the available data.
In cancer patients: In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended dose were mild or moderate musculoskeletal pain, occurring in 10%, and severe musculoskeletal pain in 3% of patients. Musculoskeletal pain is usually controlled with standard analgesics.
Less frequent undesirable effects include urinary abnormalities predominantly mild or moderate dysuria.
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of undesirable effects associated with cytotoxic chemotherapy. Undesirable effects reported with equal frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucosal inflammation, headache, cough, rash, chest pain, asthenia, pharyngolaryngeal pain, constipation and pain.
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase, alkaline phosphatase, uric acid and gamma-glutamyl transferase occurred with filgrastim in approximately 50%, 35%, 25% and 10% of patients, respectively at recommended doses.
Transient decreases in blood pressure, not requiring clinical treatment, have been reported occasionally.
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see Pharmacology: Pharmacodynamics under Actions).
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported occasionally in patients undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. The causal association with filgrastim has not been established. (See Table 3.)

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In PBPC mobilisation in normal donors: The most commonly reported undesirable effect was mild to moderate transient musculoskeletal pain.
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.
Transient, minor increases in alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase and uric acid have been reported in normal donors receiving filgrastim; these were without clinical sequelae.
Exacerbation of arthritic symptoms has been observed very rarely.
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies.
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 granulocyte-colony stimulating factors (see Precautions). (See Table 4.)

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In SCN patients: Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some their frequency tends to decrease with time.
The most frequent adverse effects attributable to filgrastim were bone pain and general musculoskeletal pain.
Other undesirable effects seen include splenomegaly, which may be progressive in a minority of cases and thrombocytopenia.
Headache and diarrhoea have been reported shortly after starting filgrastim therapy, typically in less than 10% of patients.
Anaemia and epistaxis have also been reported.
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been seen.
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. There have been very few instances of proteinuria/haematuria. (See Table 5.)

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In patients with HIV: In clinical studies, the only undesirable effects that were consistently considered to be related to filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and myalgia. The incidence of these events was similar to that reported in cancer patients.
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 hypersplenism 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. (See Table 6.)

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Post-marketing experience: Cancer patients: Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitis in patients receiving filgrastim is unknown.
Cases of Sweet's syndrome (acute febrile dermatosis) have been reported.
Exacerbation of rheumatoid arthritis has been observed in individual cases.
Pulmonary adverse effects including interstitial pneumonia, 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).
In cancer patients, hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in post-marketing experience. Overall, reports were more common after i.v. 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.
Isolated cases of sickle cell crisis have been reported in patients with sickle cell disease (see Precautions).
Pseudogout has been reported in patients with cancer treated with filgrastim.
Normal Donors: In normal donors, anaphylaxis has been reported in post-marketing experience.
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration, dyspnoea and hypoxia) have been reported in post-marketing experience (see Precautions).
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 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 filgrastim. Although this interaction has not been formally investigated, there is no evidence that such an interaction is harmful.
Caution For Usage
Special precautions for disposal and other handling: If required, Alvograstim may be diluted in glucose 50 mg/ml (5%) glucose solution for infusion.
Dilution to a final concentration less than 0.2 MU (2 micrograms) per ml is not recommended at any time.
The solution should be visually inspected prior to use. Only clear solutions without particles should be used.
For patients treated with filgrastim diluted to concentrations below 1.5 MUI (15 micrograms) 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 MUI (300 micrograms) should be given with 0.2 ml of 20% human albumin solution added.
When diluted in glucose 50 mg/ml (5%) solution for infusion, filgrastim is compatible with glass and a variety of plastics including polyvinyl chloride (PVC), polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.
Alvograstim syringes are for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Alvograstim should not be diluted with saline solutions.
Diluted filgrastim may be adsorbed to glass and plastic materials.
This medicinal product must not be mixed with other products except those mentioned in above text.
Storage
Store at 2 to 8 °C.
Shelf-Life: 2 years.
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 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
MIMS Class
Haematopoietic Agents / Supportive Care Therapy
ATC Classification
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Presentation/Packing
Soln for inj (clear, colourless solution) (pre-filled syringe) 300 mcg/mL x 1's.
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