Grastofil

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Grastofil 30 MU/0.5 mL solution for injection/infusion in pre-filled syringe 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each mL of solution contains 60 million units (MU) (equivalent to 600 micrograms [μg]) of filgrastim.  

 

Each syringe of 0.5 mL solution contains 30 MU (300 micrograms) of filgrastim  

(600 micrograms/mL). 

 

Filgrastim is a recombinant methionyl human granulocyte-colony stimulating factor produced in 

Escherichia coli (BL21) by recombinant DNA technology. 

 

Excipient with known effect  

 

Each mL of solution contains 50 mg of sorbitol (E420) (see section 4.4).  

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection/infusion.  

 

Clear, colourless solution. 

 

4. CLINCAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Grastofil is indicated for the 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 for the reduction in the 

duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow 

transplantation considered to be at increased risk of prolonged severe neutropenia.  
 

The safety and efficacy of Grastofil are similar in adults, children and adolescents receiving cytotoxic 

chemotherapy.  

   

Grastofil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs). 

 

In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute 

neutrophil count (ANC) of ≤ 0.5 x 10
9
/L, and a history of severe or recurrent infections, long term 

administration of Grastofil is indicated to increase neutrophil counts and to reduce the incidence and 

duration of infection-related events. 

 

Grastofil is indicated for the treatment of persistent neutropenia (ANC less than or equal to 

1.0 x 10
9
/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections 

when other options to manage neutropenia are inappropriate. 
 

4.2 Posology and method of administration 

 

Grastofil therapy should only be given in collaboration with an oncology centre which has experience 

in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the necessary 

diagnostic facilities. The mobilisation and apheresis procedures should be performed in collaboration 



 

3 

with an oncology-haematology centre with acceptable experience in this field and where the 

monitoring of haematopoietic progenitor cells can be correctly performed.  

 

Established cytotoxic chemotherapy  

 

Posology  

 

The recommended dose of Grastofil is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of 

Grastofil should be administered at least 24 hours after cytotoxic chemotherapy. In randomised 

clinical studies, a subcutaneous dose of 230 micrograms/m
2
/day (4.0 to 8.4 micrograms/kg/day) was 

used.  

   

Daily dosing with Grastofil 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 leukaemias, 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 

1-2 days after initiation of Grastofil therapy. However, for a sustained therapeutic response, Grastofil 

therapy should not be discontinued before the expected nadir has passed and the neutrophil count has 

recovered to the normal range. Premature discontinuation of Grastofil therapy, prior to the time of the 

expected neutrophil nadir, is not recommended.  

 

Method of administration  

 

Grastofil may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 

5% glucose solution given over 30 minutes (see section 6.6). 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.  

 

In patients treated with myeloablative therapy followed by bone marrow transplantation  

 

Posology  

 

The recommended starting dose of Grastofil is 1.0 MU/kg/day (10 micrograms/kg/day). The first dose 

of Grastofil should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 

hours after bone marrow infusion.  

 

Once the neutrophil nadir has been passed, the daily dose of Grastofil should be titrated against the 

neutrophil response as follows: 

 

Absolute neutrophil count (ANC) Grastofil dose adjustment  

ANC > 1.0 x 10
9
/L for 3 consecutive days  Reduce to 0.5 MU/kg/day (5 micrograms/kg/day)  

Then, if ANC remains > 1.0 x 10
9
/L for 3 more 

consecutive days  

Discontinue Grastofil  

If the ANC decreases to < 1.0 x 10
9
/L during the treatment period, the dose of Grastofil should be re-

escalated according to the above steps  

ANC = absolute neutrophil count  

 

Method of administration  

 

Grastofil may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 24 hour 

subcutaneous infusion. Grastofil should be diluted in 20 mL of 5% glucose solution  (see section 6.6).  

 



 

4 

For the mobilisation of peripheral blood progenitor cells (PBPC) in patients undergoing 

myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation  

 

Posology  

 

The recommended dose of Grastofil for PBPC mobilisation when used alone is 1.0 MU/kg/day (10 

micrograms/kg/day) for 5-7 consecutive days. The timing of leukapheresis: one or two leukaphereses 

on days 5 and 6 which is often sufficient. In other circumstances, additional leukaphereses may be 

necessary. Grastofil dosing should be maintained until the last leukapheresis.  

 

The recommended dose of Grastofil for PBPC mobilisation after myelosuppressive chemotherapy is 

0.5 MU/kg/day (5 micrograms/kg/day) from the first day after completion of chemotherapy until the 

expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. 

Leukapheresis should be performed during the period when the ANC rises from < 0.5 x 10
9
/L to  

> 5.0 x 10
9
/L. For patients who have not had extensive chemotherapy, one leukapheresis is often 

sufficient. In other circumstances, additional leukaphereses are recommended.  

 

Method of administration  

 

Grastofil for PBPC mobilisation when used alone Grastofil may be given as a 24 hour subcutaneous 

continuous infusion or subcutaneous injection. For infusions Grastofil should be diluted in 20 mL of 

5% glucose solution (see section 6.6).  

 

Grastofil for PBPC mobilisation after myelosuppressive chemotherapy 

Grastofil should be given by subcutaneous injection. 

 

For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation  

 

Posology  

 

For PBPC mobilisation in normal donors, Grastofil should be administered at 1.0 MU/kg/day 

(10 micrograms/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 10
6

 

CD34
+
 cells/kg recipient bodyweight.  

 

Method of administration  

 

Grastofil should be given by subcutaneous injection. 

 

In patients with severe chronic neutropenia (SCN)  

 

Posology  

 

Congenital neutropenia: the recommended starting dose is 1.2 MU/kg/day (12 micrograms/kg/day) as 

a single dose or in divided doses.  

 

Idiopathic or cyclic neutropenia:  the recommended starting dose is 0.5 MU/kg/day  

(5 micrograms/kg/day) as a single dose or in divided doses.  

 

Dose adjustment: Grastofil should be administered daily by subcutaneous injection until the neutrophil 

count has reached and can be maintained at more than 1.5 x 10
9
/L. When the response has been 

obtained, the minimal effective dose to maintain this level should be established. Long-term daily 

administration is required to maintain an adequate neutrophil count. After one to two weeks of 

therapy, the initial dose may be doubled or halved depending upon the patient's response. 

Subsequently, the dose may be individually adjusted every 1-2 weeks to maintain the average 

neutrophil count between 1.5 x 10
9
/L and 10 x 10

9
/L. A faster schedule of dose escalation may be 

considered in patients presenting with severe infections. In clinical studies, 97% of patients who 

responded had a complete response at doses of ≤ 2.4 MU/kg/day (24 micrograms/kg/day). The  



 

5 

long-term safety of administration of Grastofil at doses above 2.4 MU/kg/day (24 micrograms/kg/day) 

in patients with SCN has not been established.  

 

Method of administration  

 

Congenital, idiopathic or cyclic neutropenia: Grastofil should be given by subcutaneous injection. 

 

In patients with HIV infection  

 

Posology  

For reversal of neutropenia  

The recommended starting dose of Grastofil is 0.1 MU/kg/day (1 micrograms/kg/day)  with titration 

up to a maximum of 0.4 MU/kg/day (4 micrograms/kg/day) until a normal neutrophil count is reached 

and can be maintained (ANC > 2.0 x 10
9
/L). In clinical studies, > 90% of patients responded at these 

doses, achieving a reversal of neutropenia in a median of 2 days.  

 

In a small number of patients (< 10%), doses up to 1.0 MU/kg/day (10 micrograms/kg/day) were 

required to achieve reversal of neutropenia. 

 

For 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 micrograms/day) is recommended. Further dose adjustment may be necessary, as determined by 

the patient's ANC, to maintain the neutrophil count at > 2.0 x 10
9
/L. In clinical studies, dosing with 30 

MU/day (300 micrograms/day) on 1 - 7 days per week was required to maintain the ANC 

 > 2.0 x 10
9
/L, with the median dose frequency being 3 days per week. Long-term administration may 

be required to maintain the ANC > 2.0 x 10
9
/L.  

 

Method of administration  

 

Reversal of neutropenia or maintaining normal neutrophil counts: Grastofil should be given by 

subcutaneous injection. 

 

Special populations  

 

Elderly patients  

Clinical studies with filgrastim have included a small number of elderly patients but special studies 

have not been performed in this group and therefore specific posology recommendations cannot be 

made. 

 

Patients with 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 of patients studied in a SCN trial program, were under 18 years of age. The efficacy 

of treatment was clear for this age group, which included most patients with congenital neutropenia. 

There were no differences in the safety profiles for paediatric patients treated for SCN. 

 

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 

similar in both adults, children and adolescents receiving cytotoxic chemotherapy. 

 

The dose recommendations in paediatric patients are the same as those in adults receiving 

myelosuppressive cytotoxic chemotherapy. 

 



 

6 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

Traceability  

 

In order to improve the traceability of biological medicinal products, the name and the batch number 

of the administered product should be clearly recorded.   

 

Special warnings and precautions across indications 

 

Hypersensitivity 

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have 

been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with 

clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of 

hypersensitivity to filgrastim or pegfilgrastim.  

 

Pulmonary adverse reactions 

Pulmonary adverse reactions, 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). Filgrastim 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 hemoconcentration. Patients who develop symptoms of capillary leak 

syndrome should be closely monitored and receive standard symptomatic treatment, which may 

include a need for intensive care (see section 4.8). 

 

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 filgrastim. Some cases of splenic rupture were 

fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A 

diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper 

abdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop the 

progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a 

splenectomy was required. 

 

Malignant cell growth 

Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects 

may be seen on some non-myeloid cells in vitro. 

 

Myelodysplastic syndrome or Chronic myeloid leukemia 

The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or 

chronic myelogenous 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. 



 

7 

Acute myeloid leukaemia 

In view of limited safety and efficacy data in patients with secondary 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. 

 

Thrombocytopenia 

Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be 

monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be 

given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic 

neutropenia who develop thrombocytopenia (platelet count < 100 x 10
9
/l). 

 

Leukocytosis 

White blood cell counts of 100 x 10
9
/L or greater have been observed in less than 5% of cancer 

patients receiving filgrastim at doses above 0.3 MU/kg/day (3 µg/kg/day). No undesirable effects 

directly attributable to this degree of leukocytosis have been reported. However, in view of the 

potential risks associated with severe leukocytosis, a white blood cell count should be performed at 

regular intervals during filgrastim therapy. If leukocyte counts exceed 50 x 10
9
/L after the expected 

nadir, filgrastim should be discontinued immediately. When administered for PBPC mobilisation, 

filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to  

> 70 x 10
9
/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. The 

symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory 

markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by 

CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.  

 

Special warning 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 filgrastim in patients with 

sickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim 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 filgrastim for more than 6 months. 

 

Special precautions in cancer patients 

 

Filgrastim 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 medicinal 

products may lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic 

effects (please refer to the prescribing information of the specific chemotherapy medicinal products 

used). 

 



 

8 

Effect of chemotherapy on erythrocytes and thrombocytes 

Treatment with filgrastim 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 medicinal products which are 

known to cause severe thrombocytopenia. 

 

The use of filgrastim-mobilised 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 (such 

as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 

by tumour). 

 

Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 

reported occasionally in patients undergoing high dose chemotherapy followed by transplantation. 

 

There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF 

after allogeneic bone marrow transplantation (see section 4.8 and 5.1). 

 

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 

(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 optimal 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 medicinal products  

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 10
6
 CD34

+
 cells/kg) or 

acceleration of platelet recovery to the same degree. 

 

Some cytotoxic medicinal products  exhibit particular toxicities to the haematopoietic progenitor pool 

and may adversely affect progenitor mobilisation. Medicinal products 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 

carmustine (BCNU) together with filgrastim has been shown to be effective for progenitor 

mobilisation. When peripheral blood progenitor cell 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 



 

9 

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 re-infused and the rate of 

platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. 

 

The recommendation of a minimum yield of ≥ 2.0 x 10
6 

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. 

 

Special precautions in normal donors undergoing peripheral blood progenitor cell mobilisation 

 

Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be 

considered for the purposes of allogeneic stem cell transplantation. 

 

PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory 

eligibility criteria for stem cell donation with special attention to haematological values and infectious 

diseases.  

 

The safety and efficacy of filgrastim has not been assessed in normal donors less than 16 years or 

greater than 60 years of age.  

 

Transient thrombocytopenia (platelets < 100 x 10
9
/L) following filgrastim administration and 

leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets  

< 50 x 10
9/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 10
9
/L prior to leukapheresis; in general apheresis should not be performed if platelets are  

< 75 x 10
9
/L.  

 

Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 

in haemostasis.  

 

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. Nevertheless, a risk of promotion of a malignant myeloid 

clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and 

tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 

 

Special precautions in recipients of allogeneic PBPC 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. 

 

Special precautions in SCN patients 

 

Filgrastim should not be administered to patients with severe congenital neutropenia who develop 

leukaemia or have evidence of leukaemic evolution. 

 

Blood cell counts 

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 



 

10 

disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell 

counts with differential and platelet counts and an evaluation of bone marrow morphology and 

karyotype should be performed prior to treatment. 

 

There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in 

clinical trial patients with SCN treated with filgrastim. This observation has only been made in 

patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease 

and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had 

normal cytogenetic evaluations at baseline was 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 such as viral infections should be excluded. 

Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis 

should be performed to monitor this event. 

 

The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 

established. 

 

Special precautions in patients with HIV infection  

 

Blood cell counts 

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 to 3 days of 

filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice 

weekly 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 microgram)/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 medicinal products. As a result of the potential to receive higher doses or a greater 

number of these medicinal products with filgrastim therapy, the patient may be at higher risk of 

developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see 

above). 

 

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. 
 

All patients 

 

This medicinal product contains 50 mg sorbitol. Patients with hereditary fructose intolerance (HFI) 

must not be given this medicinal product unless strictly necessary.  

  

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 

‘sodium-free’. 

 



 

11 

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 

may cause allergic reactions. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

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 hours before to 24 hours 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 studies. 

 

Since lithium promotes the release of neutrophils, it 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. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

There are no or limited amount of data from the use of filgrastim in pregnant women. Studies in 

animals have shown reproductive toxicity. An increased incidence of embryo-loss has been observed 

in rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity (see 

section 5.3).. There are reports in the literature where the transplacental passage of filgrastim in 
pregnant women has been demonstrated.  

 

Filgrastim is not recommended during pregnancy. 

 

Breast-feeding 

 

It is unknown whether filgrastim / metabolites are excreted in human milk. A risk to the 

newborns/infants cannot be excluded. A decision must be made whether to discontinue  

breast-feeding or to discontinue/abstain from filgrastim therapy taking into account the benefit of 

breast-feeding for the child and the benefit of therapy for the woman. 

 

Fertility 

 

Filgrastim did not affect reproductive performance or fertility in male or female rats (see section 5.3). 

The impact of filgrastim on human fertility is not known. 

 

4.7 Effects on ability to drive and use machines 

 

Filgrastim has minor influence on the ability to drive and use machines. Dizziness may occur 

following the administration of filgrastim (see section 4.8). 

 

4.8 Undesirable effects 

 

Summary of the safety profile  

 

The most serious adverse reactions that may occur during filgrastim treatment include: anaphylactic 

reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary 

leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or 

leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral 

blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease. 



 

12 

The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes 

bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal 

chest pain, neck pain), anaemia, vomiting, and nausea. In clinical studies in cancer patients 

musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients. 

 

Tabulated list of adverse reactions 

 

The data in the tables below describe adverse reactions reported from clinical studies and spontaneous 

reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing 

seriousness.  

 
MedDRA system 

organ class 

Adverse reactions 

Very common 

(≥ 1/10) 

Common 

(≥ 1/100 to < 

1/10) 

Uncommon 

(≥ 1/1,000 to < 

1/100) 

Rare 

(≥ 1/10,000 to < 

1/1,000) 

Infections and 

infestations 

 Sepsis 

 

Bronchitis 

 

Upper 

respiratory tract 

infection 

 

Urinary tract 

infection 

  

Blood and 

lymphatic system 

disorders 

Thrombocytopenia 

 

Anaemia
e 

Splenomegaly
a 

 

Haemoglobin 

decreased
e
 

Leukocytosis
a 

 

 

 

Splenic rupture
a 

 

Sickle cell anaemia with 

crisis 

Immune system 

disorders 

  Hypersensitivity 

 

Drug 

hypersensitivity
a
  

 

Graft versus Host 

Disease
b
 

Anaphylactic reaction 

Metabolism and 

nutrition 

disorders 

 

 

Decreased 

appetite
a 

 

Blood lactate 

dehydrogenase 

increased  

 

Hyperuricaemia 

 

Blood uric acid 

increased  

 

Blood glucose decreased  

 

Pseudogout
a
  

(Chondrocalcinosis 

Pyrophosphate)  

 

Fluid volume 

disturbances 

Psychiatric 

disorders 

 Insomnia   

Nervous system 

disorders 

Headache
a
 Dizziness 

 

Hypoaesthesia  

 

Paraesthesia 

  

Vascular 

Disorders 

 Hypertension 

 

Hypotension 

Veno-occlusive 

disease
d
 

 
 

Capillary leak syndrome
a 

 

Aortitis 

Respiratory, 

thoracic and 

mediastinal 

disorders 

 

 

Haemoptysis
 

 

Dyspnoea 

 

Cough
a  

 

Acute respiratory 

distress syndrome
a  

 

Respiratory 

failure
a  

 

 



 

13 

MedDRA system 

organ class 

Adverse reactions 

Very common 

(≥ 1/10) 

Common 

(≥ 1/100 to < 

1/10) 

Uncommon 

(≥ 1/1,000 to < 

1/100) 

Rare 

(≥ 1/10,000 to < 

1/1,000) 

Oropharyngeal 

pain
a, e

  

 

Epistaxis 

Pulmonary 

oedema
a
  

 

Pulmonary 

haemorrhage 

 

Interstitial lung 

disease
a
  

 

Lung infiltration
a
  

 

Hypoxia 

Gastrointestinal 

disorders 

Diarrhoea
a, e  

 

Vomiting
a, e

  

 

Nausea
a
 

Oral Pain 

 

Constipation
e
  

 

  

Hepatobiliary 

disorders 

 

 

Hepatomegaly 

 

Blood alkaline 

phosphatase 

increased 

 

Aspartate 

aminotransferase 

increased 

 

Gamma-glutamyl 

transferase 

increased 

 

Skin and 

subcutaneous 

tissue disorders 

Alopecia
a
 

 

Rash
a
  

 

Erythema 

 

Rash maculo- 

papular 

 

Cutaneous vasculitis
a 

 

Sweets syndrome 

(acute febrile 

neutrophilic dermatosis) 

Musculoskeletal 

and connective 

tissue disorders 

Musculoskeletal 

pain
c
 

Muscle spasms Osteoporosis Bone density decreased  

 

Exacerbation of 

rheumatoid arthritis 

Renal and 

urinary disorders 

 Dysuria 

 

Haematuria 

Proteinuria 

 

Glomerulonephritis 

 

Urine abnormality 

General disorders 

and 

administration 

site conditions 

Fatigue
a
  

 

Mucosal 

inflammation
a 

 

Pyrexia 

Chest pain
a 

 

Pain
a 

 

Asthenia
a 

 

Malaise
e
  

 

Oedema 

peripheral
e 

Injection site 

reaction 

 

Injury, poisoning 

and procedural 

complications 

 Transfusion 

reaction
e
 

  

a See section: Description of selected adverse reactions  
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section 

Description of selected adverse reactions)  
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck 

pain  
d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC mobilization  
e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the 

underlying malignancy or cytotoxic chemotherapy  

 



 

14 

Description of selected adverse reactions 

 

Hypersensitivity 

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and 

hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in 

post-marketing experience. Overall, reports were more common after intravenous 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.  

 

Pulmonary adverse reactions 

In clinical studies and the post-marketing setting pulmonary adverse reactions 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 

section 4.4). 

 

Splenomegaly and splenic rupture 

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. 

Some cases of splenic rupture were fatal (see section 4.4).   

 

Capillary leak syndrome 

Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor use. 

These have generally occurred in patients with advanced malignant diseases, sepsis, using multiple 

chemotherapy medicinal products or undergoing apheresis (see section 4.4). 

 

Cutaneous vasculitis 

Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitis 

in patients receiving filgrastim is unknown. During long-term use cutaneous vasculitis has been 

reported in 2% of SCN patients. 

 

Leukocytosis 

Leukocytosis (WBC > 50 x 10
9
/L) was observed in 41% of normal donors and transient 

thrombocytopenia (platelets < 100 x 10
9
/L) following filgrastim treatment and leukapheresis was 

observed in 35% of donors (see section 4.4). 

 

Sweets syndrome 

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients 

treated with filgrastim. 

 

Pseudogout (chondrocalcinosis pyrophosphate) 

Pseudogout (chondrocalcinosis pyrophosphate) has been reported in cancer patients treated with 

filgrastim. 

 

GvHD 

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 

marrow transplantation (see sections 4.4 and 5.1). 

 

Paediatric population  

 

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 

similar in both adults, children and adolescents 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.  

Other special populations  

 

Elderly 



 

15 

No overall differences in safety or effectiveness were observed between subjects over 65 years of age 

compared to younger adult (>18 years of age) subjects receiving cytotoxic chemotherapy and clinical 

experience has not identified differences in the responses between elderly and younger adult patients. 

There is insufficient data to evaluate filgrastim use in elderly subjects for other approved Grastofil 

indications.  

  

Paediatric SCN patients 

Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe 

chronic neutropenia receiving chronic treatment with filgrastim.  

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

The effects of Grastofil 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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC code: L03AA02 

 

Grastofil is a biosimilar medicinal product. Detailed information is available on the website of the 

European Medicines Agency http://www.ema.europa.eu.  

 

Pharmacodynamic effects 

 

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils 

from the bone marrow. Grastofil containing r-metHuG-CSF (filgrastim) causes marked increases in 

peripheral blood neutrophil counts within 24 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 

peripheral blood. These autologous 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/


 

16 

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 randomised  studies, 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.  

 

Relative risk (95% CI) of GvHD and TRM following treatment with G-CSF after bone 

marrow (BM) transplantation 

Publication  Period of 

study 

N Acute grade          

II - IV GvHD 

Chronic 

GvHD 

TRM 

Meta-Analysis   

(2003)  

1986 - 2001
a
 1198  1.08 

(0.87, 1.33)  

1.02 

(0.82, 1.26)  

0.70 

(0.38, 1.31)  

European 

Retrospective  

Study (2004)  

1992 – 2002
b
 1789  1.33 

    (1.08, 1.64)  

1.29 

(1.02, 1.61)  

1.73 

(1.30, 2.32)  

International 

Retrospective  

Study (2006)  

1995 – 2000
b
 2110  1.11 

  (0.86, 1.42)  

1.10 

(0.86, 1.39)  

1.26 

(0.95, 1.67)  

a
 

Analysis includes studies involving BM transplant during this period; some studies used GM-CSF  
b

 

Analysis includes patients receiving BM transplant during this period  

 

Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC 

transplantation  

 

In normal donors, a 10 micrograms/kg/day dose administered subcutaneously for 4 - 5 consecutive 

days allows a collection of ≥ 4 x 10
6 

 

CD34
+
 cells/kg recipient body weight in the majority of the 

donors after two leukaphereses.  

 

Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic 

neutropenia) induces a sustained increase in ANCs 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 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. 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Following subcutaneous administration of recommended doses, serum concentrations were maintained 

above 10 ng/mL for 8 - 16 hours.  

Distribution  

 

The volume of distribution in blood is approximately 150 mL/kg.  



 

17 

 

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 half-lives.  

 

Linearity 

 

There is a positive linear correlation between the dose and the serum concentration of filgrastim, 

whether administered intravenously or subcutaneously.  

 

5.3 Preclinical safety data 

 

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed 

changes attributable to the expected pharmacological actions including increases in leukocytes, 

myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These 

changes all reversed after discontinuation of treatment. 

 

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous (80 

μg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally 

toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size 

and fetal weight were observed. 

 

Based on reported data for another filgrastim product similar to Grastofil, comparable findings plus 

increased fetal malformations were observed at 100 μg/kg/day, a maternally toxic dose which 

corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients 

treated with the clinical dose of 5 μg/kg/day. The no observed adverse effect level for embryo-fetal 

toxicity in this study was 10 μg/kg/day, which corresponded to a systemic exposure of approximately 

3-5 times the exposures observed in patients treated with the clinical dose. 

 

In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 μg/kg/day. Offspring of 

rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external 

differentiation and growth retardation (≥20 μg/kg/day) and slightly reduced survival rate  

(100 μg/kg/day).  

 

Filgrastim had no observed effect on the fertility of male or female rats. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Glacial acetic acid Sodium hydroxide 

Sorbitol (E420)  

Polysorbate 80 

Water for injections 

 

6.2 Incompatibilities 

 

Diluted filgrastim may be adsorbed to glass and plastic materials. 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6.  

 



 

18 

6.3 Shelf life 

 

3 years. 

 

Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 

24 hours at 2 °C to 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 hours at 2 °C to 8 °C, unless 

dilution has taken place in controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2 °C – 8 °C). Do not freeze.  

 

Keep the syringe in the outer carton in order to protect from light. 

 

Accidental one-time exposure to freezing temperatures does not adversely affect the stability of 

Grastofil. If exposure has been greater than 24 hours or frozen more than once then Grastofil should 

not be used. 

 

Within its shelf-life and for the purpose of ambulatory use, the patient may remove Grastofil from the 

refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 days. 

At the end of this period, Grastofil should not be put back in the refrigerator and should be disposed of 

in accordance with local requirements. 

 

For storage conditions of the diluted medicinal product, see section 6.3. 

 

6.5 Nature and contents of container  

 

Type I glass pre-filled syringe with permanently attached stainless steel needle in the tip and 1/40 

printed markings for graduations from 0.1 mL to 1 mL on the barrel. The needle cover of the pre-filled 

syringe contains dry natural rubber (latex, see section 4.4). Each pre-filled syringe contains 0.5 mL 

solution. 

 

Pack sizes: Cartons containing 1 or 5 pre-filled syringes. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

If required, Grastofil may be diluted in 5% glucose solution for injection/infusion. Dilution to a final 

concentration less than 0.2 MU (2 µg) 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. Do not shake.  

 

For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per mL, human 

serum albumin (HSA) should be added to a final concentration of 2 mg/mL. Example: In a final 

injection volume of 20 mL, total doses of filgrastim less than 30 MU (300 µg) should be given with 

0.2 mL of 200 mg/mL (20%) human albumin solution added. 

Grastofil contains no preservative. In view of the possible risk of microbial contamination, Grastofil 

pre-filled syringes are for single use only. 

 

When diluted in 5% glucose, Grastofil is compatible with glass and a variety of plastics including 

PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 

 



 

19 

Disposal  

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/877/001 

EU/1/13/877/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 18 October 2013 

Date of latest renewal: 4 October 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 

 

http://www.ema.europa.eu/


 

20 

1. NAME OF THE MEDICINAL PRODUCT 

 

Grastofil 48 MU/0.5 mL solution for injection/infusion in pre-filled syringe 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each mL of solution contains 96 million units (MU) (equivalent to 960 micrograms [μg]) of filgrastim.  

 

Each syringe of 0.5 mL solution contains 48 MU (480 micrograms) of filgrastim  

(960 micrograms/mL). 

 

Filgrastim is a recombinant methionyl human granulocyte-colony stimulating factor produced in 

Escherichia coli (BL21) by recombinant DNA technology. 

 

Excipient with known effect  

 

Each mL of solution contains 50 mg of sorbitol (E420) (see section 4.4).  

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection/infusion. 

 

Clear, colourless solution. 

 

 

4. CLINCAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Grastofil is indicated for the 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 for the reduction in the 

duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow 

transplantation considered to be at increased risk of prolonged severe neutropenia.  
 

The safety and efficacy of Grastofil are similar in adults, children and adolescents  receiving cytotoxic 

chemotherapy.  

   

Grastofil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs). 

 

In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute 

neutrophil count (ANC) of ≤ 0.5 x 10
9
/L, and a history of severe or recurrent infections, long term 

administration of Grastofil is indicated to increase neutrophil counts and to reduce the incidence and 

duration of infection-related events. 

 

Grastofil is indicated for the treatment of persistent neutropenia (ANC less than or equal to  

1.0 x 10
9
/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections 

when other options to manage neutropenia are inappropriate. 
 

4.2 Posology and method of administration 

 

Grastofil therapy should only be given in collaboration with an oncology centre which has experience 

in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the necessary 



 

21 

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.  

 

Established cytotoxic chemotherapy  

 

Posology 

 

The recommended dose of Grastofil is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of 

Grastofil should be administered at least 24 hours after cytotoxic chemotherapy.  In randomised 

clinical studies, a subcutaneous dose of 230 micrograms/m
2
/day (4.0 to 8.4 micrograms/kg/day) was 

used.  

 

Daily dosing with Grastofil 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 leukaemias, 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 

1-2 days after initiation of Grastofil therapy. However, for a sustained therapeutic response, Grastofil 

therapy should not be discontinued before the expected nadir has passed and the neutrophil count has 

recovered to the normal range. Premature discontinuation of Grastofil therapy, prior to the time of the 

expected neutrophil nadir, is not recommended.  

 

Method of Administration  

 

Grastofil may be administered as a daily subcutaneous injection or as a daily intravenous infusion 

diluted in 5% glucose solution given over 30 minutes (see section 6.6). 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.  

 

In patients treated with myeloablative therapy followed by bone marrow transplantation  

 

Posology 

 

The recommended starting dose of Grastofil is 1.0 MU/kg/day (10 micrograms/kg/day). The first dose 

of Grastofil should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 

hours after bone marrow infusion.  

 

Once the neutrophil nadir has been passed, the daily dose of Grastofil should be titrated against the 

neutrophil response as follows: 

 

Absolute neutrophil count (ANC) Grastofil dose adjustment  

ANC > 1.0 x 10
9
/L for 3 consecutive days  Reduce to 0.5 MU/kg/day (5 micrograms/kg/day)  

Then, if ANC remains > 1.0 x 10
9
/L for 3 more 

consecutive days  

Discontinue Grastofil  

If the ANC decreases to < 1.0 x 10
9
/L during the treatment period, the dose of Grastofil should be re-

escalated according to the above steps  

ANC = absolute neutrophil count  

 



 

22 

Method of Administration  

 

Grastofil may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 24 hour 

subcutaneous infusion. Grastofil should be diluted in 20 mL of 5% glucose solution  (see section 6.6).  

 

For the mobilisation of peripheral blood progenitor cells (PBPC) in patients undergoing 

myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation  

 

Posology 

 

The recommended dose of Grastofil for PBPC mobilisation when used alone is 1.0 MU/kg/day 

(10 micrograms/kg/day) for 5-7 consecutive days. The timing of leukapheresis: one or two 

leukaphereses on days 5 and 6 which is often sufficient. In other circumstances, additional 

leukaphereses may be necessary. Grastofil dosing should be maintained until the last leukapheresis.  

 

The recommended dose of Grastofil for PBPC mobilisation after myelosuppressive chemotherapy is 

0.5 MU/kg/day (5 micrograms/kg/day) from the first day after completion of chemotherapy until the 

expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. 

Leukapheresis should be performed during the period when the ANC rises from < 0.5 x 10
9
/L to  

> 5.0 x 10
9
/L. For patients who have not had extensive chemotherapy, one leukapheresis is often 

sufficient. In other circumstances, additional leukaphereses are recommended.  

 

Method of administration  

 

Grastofil for PBPC mobilisation when used alone 

 

Grastofil may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For 

infusions Grastofil should be diluted in 20 mL of 5% glucose solution (see section 6.6).  

 

Grastofil for PBPC mobilisation after myelosuppressive chemotherapy 

 

Grastofil should be given by subcutaneous injection. 

 

For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation  

 

Posology  

 

For PBPC mobilisation in normal donors, Grastofil should be administered at 1.0 MU/kg/day 

(10 micrograms/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 10
6

 

CD34
+
 cells/kg recipient bodyweight.  

 

Method of administration  

 

Grastofil should be given by subcutaneous injection. 

 

In patients with severe chronic neutropenia (SCN)  

 

Posology 

 

Congenital neutropenia: the recommended starting dose is 1.2 MU/kg/day (12 micrograms/kg/day) as 

a single dose or in divided doses. Idiopathic or cyclic neutropenia: the recommended starting dose is 

0.5 MU/kg/day (5 micrograms/kg/day) as a single dose or in divided doses.  

 

Dose adjustment: Grastofil should be administered daily by subcutaneous injection until the neutrophil 

count has reached and can be maintained at more than 1.5 x 10
9
/L. When the response has been 

obtained, the minimal effective dose to maintain this level should be established. Long-term daily 

administration is required to maintain an adequate neutrophil count. After one to two weeks of 



 

23 

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 10
9
/L and 10 x 10

9
/L.A faster schedule of dose escalation may be 

considered in patients presenting with severe infections. In clinical studies, 97% of patients who 

responded had a complete response at doses of ≤ 2.4 MU/kg/day (24 micrograms/kg/day). The  

long-term safety of administration of Grastofilat doses above 2.4 MU/kg/day (24 micrograms/kg/day) 

in patients with SCN has not been established.  

 

Method of Administration 

 

Congenital, idiopathic or cyclic neutropenia: Grastofil should be given by subcutaneous injection. 

 

In patients with HIV infection  

 

Posology  

 

For reversal of neutropenia  

The recommended starting dose of Grastofil is 0.1 MU/kg/day (1 micrograms/kg/day) with titration up 

to a maximum of 0.4 MU/kg/day (4 micrograms/kg/day) until a normal neutrophil count is reached 

and can be maintained (ANC > 2.0 x 10
9
/L). In clinical studies, > 90% of patients responded at these 

doses, achieving a reversal of neutropenia in a median of 2 days.  

 

In a small number of patients (< 10%), doses up to 1.0 MU/kg/day (10 micrograms/kg/day) were 

required to achieve reversal of neutropenia. 

 

For 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 micrograms/day) is recommended. Further dose adjustment may be necessary, as determined by 

the patient's ANC, to maintain the neutrophil count at > 2.0 x 10
9
/L. In clinical studies, dosing with 30 

MU/day (300 micrograms/day) on 1 - 7 days per week was required to maintain the ANC  

> 2.0 x 10
9
/L, with the median dose frequency being 3 days per week. Long-term administration may 

be required to maintain the ANC > 2.0 x 10
9
/L.  

 

Method of Administration 

 

Reversal of neutropenia or maintaining normal neutrophil counts: Grastofil should be given by 

subcutaneous injection. 

 

Special populations  

 

Elderly patients  

Clinical studies with filgrastim have included a small number of elderly patients but special studies 

have not been performed in this group and therefore specific posology recommendations cannot be 

made. 

 

Patients with 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 of patients studied in a SCN trial program, were under 18 years of age. The efficacy 

of treatment was clear for this age group, which included most patients with congenital neutropenia. 

There were no differences in the safety profiles for paediatric patients treated for SCN. 

 

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 



 

24 

similar in both adults, children and adolescents  receiving cytotoxic chemotherapy. 

 

The dose recommendations in paediatric patients are the same as those in adults receiving 

myelosuppressive cytotoxic chemotherapy. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

Traceability  

 

In order to improve the traceability of biological medicinal products, the name and the batch number 

of the administered product should be clearly recorded.  

 

Special warnings and precautions across indications 

 

Hypersensitivity 

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have 

been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with 

clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of 

hypersensitivity to filgrastim or pegfilgrastim.  

 

Pulmonary adverse reactions 

Pulmonary adverse reactions, 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). Filgrastim 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 hemoconcentration. Patients who develop symptoms of capillary leak 

syndrome should be closely monitored and receive standard symptomatic treatment, which may 

include a need for intensive care (see section 4.8). 

 

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 filgrastim. Some cases of splenic rupture were 

fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A 

diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper 

abdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop the 

progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a 

splenectomy was required. 

 

Malignant cell growth 

Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects 

may be seen on some non-myeloid cells in vitro. 



 

25 

Myelodysplastic syndrome or Chronic myeloid leukemia 

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. 

 

Acute myeloid leukaemia 

In view of limited safety and efficacy data in patients with secondary 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. 

 

Thrombocytopenia 

Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be 

monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be 

given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic 

neutropenia who develop thrombocytopenia (platelet count < 100 x 10
9
/l). 

 

Leukocytosis 

White blood cell counts of 100 x 10
9
/L or greater have been observed in less than 5% of cancer 

patients receiving filgrastim at doses above 0.3 MU/kg/day (3 µg/kg/day). No undesirable effects 

directly attributable to this degree of leukocytosis have been reported. However, in view of the 

potential risks associated with severe leukocytosis, a white blood cell count should be performed at 

regular intervals during filgrastim therapy. If leukocyte counts exceed 50 x 10
9
/L  after the expected 

nadir, filgrastim should be discontinued immediately. When administered for PBPC mobilisation, 

filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to  

> 70 x 10
9
/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. The 

symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory 

markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by 

CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.  

 

Special warning 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 filgrastim in patients with 

sickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim 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 filgrastim for more than 6 months. 

 

Special precautions in cancer patients 

 

Filgrastim 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 



 

26 

tumour outcome has not been demonstrated and intensified doses of chemotherapeutic medicinaal 

products may lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic 

effects (please refer to the prescribing information of the specific chemotherapy medicinal products 

used). 

 

Effect of chemotherapy on erythrocytes and thrombocytes 

Treatment with filgrastim 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 medicinal products which are 

known to cause severe thrombocytopenia. 

 

The use of filgrastim-mobilised 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 (such 

as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 

by tumour). 

Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 

reported occasionally in patients undergoing high dose chemotherapy followed by transplantation. 

There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF 

after allogeneic bone marrow transplantation (see section 4.8 and 5.1). 

 

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 

(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 optimal 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 medicinal products  

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 10
6
 CD34

+
 cells/kg) or 

acceleration of platelet recovery to the same degree. 

 

Some cytotoxic medicinal products exhibit particular toxicities to the haematopoietic progenitor pool 

and may adversely affect progenitor mobilisation. Medicinal products 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 

carmustine (BCNU) together with filgrastim has been shown to be effective for progenitor 

mobilisation. When peripheral blood progenitor cell 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. 

 



 

27 

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 re-infused and the rate of 

platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. 

 

The recommendation of a minimum yield of ≥ 2.0 x 10
6 

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. 

 

Special precautions in normal donors undergoing peripheral blood progenitor cell mobilisation 

 

Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be 

considered for the purposes of allogeneic stem cell transplantation. 

 

PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory 

eligibility criteria for stem cell donation with special attention to haematological values and infectious 

diseases.  

 

The safety and efficacy of filgrastim has not been assessed in normal donors less than 16 years or 

greater than 60 years of age.  

 

Transient thrombocytopenia (platelets < 100 x 10
9
/L) following filgrastim administration and 

leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets  

< 50 x 10
9/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 10
9
/L prior to leukapheresis; in general apheresis should not be performed if platelets are  

< 75 x 10
9
/L.  

 

Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 

in haemostasis.  

 

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. Nevertheless, a risk of promotion of a malignant myeloid 

clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and 

tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 

 

Special precautions in recipients of allogeneic PBPC 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. 

 

Special precautions in SCN patients 

 

Filgrastim should not be administered to patients with severe congenital neutropenia who develop 

leukaemia or have evidence of leukaemic evolution. 

 

Blood cell counts 

Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 

which require close monitoring of cell counts. 



 

28 

Transformation to leukaemia or myelodysplastic syndrome 

Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic 

disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell 

counts with differential and platelet counts and an evaluation of bone marrow morphology and 

karyotype should be performed prior to treatment. 

 

There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in 

clinical trial patients with SCN treated with filgrastim. This observation has only been made in 

patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease 

and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had 

normal cytogenetic evaluations at baseline was 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 such as viral infections should be excluded. 

 

Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis 

should be performed to monitor this event. 

 

The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 

established. 

 

Special precautions in patients with HIV infection 

 

Blood cell counts 

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 to 3 days of 

filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice 

weekly 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 microgram)/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 medicinal products. As a result of the potential to receive higher doses or a greater 

number of these medicinal products with filgrastim therapy, the patient may be at higher risk of 

developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see 

above). 

 

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. 

 

All patients 

 

This medicinal product contains 50 mg sorbitol. Patients with hereditary fructose intolerance (HFI) 

must not be given this medicinal product unless strictly necessary. 
 



 

29 

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 

‘sodium-free’. 

 

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 

may cause allergic reactions. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

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 hours before to 24 hours 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 studies. 

 

Since lithium promotes the release of neutrophils, it 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. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

There are no or limited amount of data from the use of filgrastim in pregnant women. Studies in 

animals have shown reproductive toxicity.  An increased incidence of embryo-loss has been observed 

in rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity (see 

section 5.3).  There are reports in the literature where the transplacental passage of filgrastim in 
pregnant women has been demonstrated.  

 

Filgrastim is not recommended during pregnancy. 

 

Breast-feeding 

 

It is unknown whether filgrastim / metabolites are excreted in human milk. A risk to the 

newborns/infants cannot be excluded. A decision must be made whether to discontinue  

breast-feeding or to discontinue/abstain from filgrastim therapy taking into account the benefit of 

breast-feeding for the child and the benefit of therapy for the woman. 

 

Fertility 

 

Filgrastim did not affect reproductive performance or fertility in male or female rats (see section 5.3). 

The impact of filgrastim on human fertility is not known. 

 

4.7 Effects on ability to drive and use machines 

 

Filgrastim has minor influence on the ability to drive and use machines. Dizziness may occur 

following the administration of filgrastim (see section 4.8). 

 

4.8 Undesirable effects 

 

Summary of the safety profile  

 

The most serious adverse reactions that may occur during filgrastim treatment include: anaphylactic 

reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary 



 

30 

leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or 

leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral 

blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease. 

 

The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes 

bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal 

chest pain, neck pain), anaemia, vomiting, and nausea. In clinical studies in cancer patients 

musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients. 

 

Tabulated list of adverse reactions 

 

The data in the tables below describe adverse reactions reported from clinical studies and spontaneous 

reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing 

seriousness.    

 
MedDRA system 

organ class 

Adverse reactions 

Very common 

(≥ 1/10) 

Common 

(≥ 1/100 to < 

1/10) 

Uncommon 

(≥ 1/1,000 to < 

1/100) 

Rare 

(≥ 1/10,000 to < 

1/1,000) 

Infections and 

infestations 

 Sepsis 

 

Bronchitis 

 

Upper respiratory 

tract infection 

 

Urinary tract 

infection 

  

Blood and 

lymphatic system 

disorders 

Thrombocytopenia 

 

Anaemia
e
 

Splenomegaly
a 

 

Haemoglobin 

decreased
e
 

Leukocytosis
a 

 

Splenic rupture
a 

 

Sickle cell anaemia 

with crisis 

Immune system 

disorders 

  Hypersentivity 

 

Drug 

hypersensitivity
a
  

 

Graft versus Host 

Disease
b
 

Anaphylactic 

reaction 

Metabolism and 

nutrition 

disorders 

 Decreased 

appetite
a 

 

Blood lactate 

dehydrogenase 

increased  

 

Hyperuricaemia 

 

Blood uric acid 

increased  

 

Blood glucose 

decreased  

 

Pseudogout
a
  

(Chondrocalcinosis 

Pyrophosphate)  

 

Fluid volume 

disturbances 

Psychiatric 

disorders 

 Insomnia   

Nervous system 

disorders 

Headache
a
 Dizziness 

 

Hypoaesthesia  

 

Paraesthesia 

  

Vascular 

Disorders 

 Hypertension 

 

Hypotension 

Veno-occlusive 

disease
d
 

 

Capillary leak 

syndrome
a 

 

Aortitis 

Respiratory, 

thoracic and 

 Haemoptysis
 

 
Acute respiratory 

distress syndrome
a  

 



 

31 

mediastinal 

disorders 

Dyspnoea 

 

Cough
a  

 

Oropharyngeal 

pain
a, e

  

 

Epistaxis 

 

Respiratory failure
a  

 

Pulmonary oedema
a
  

 

Pulmonary 

haemorrhage 

 

Interstitial lung 

disease
a
  

 

Lung infiltration
a
  

 

Hypoxia 

Gastrointestinal 

disorders 

Diarrhoea
a, e  

 

Vomiting
a, e

  

 

Nausea
a
 

Oral Pain 

 

Constipation
e
  

 

  

Hepatobiliary 

disorders 

 Hepatomegaly 

 

Blood alkaline 

phosphatase 

increased 

 

Aspartate 

aminotransferase 

increased 

 

Gamma-glutamyl 

transferase increased 

 

Skin and 

subcutaneous 

tissue disorders 

Alopecia
a
 

 

Rash
a
  

 

Erythema 

 

Rash maculo- 

papular 

 

Cutaneous vasculitis
a 

 

Sweets syndrome 

(acute febrile 

neutrophilic 

dermatosis) 

Musculoskeletal 

and connective 

tissue disorders 

Musculoskeletal 

pain
c
 

Muscle spasms  Osteoporosis Bone density 

decreased  

 

Exacerbation of 

rheumatoid arthritis 

Renal and 

urinary disorders 

 Dysuria 

 

Haematuria 

Proteinuria 

 

 

Glomerulonephritis 

 

Urine abnormality 

General disorders 

and 

administration 

site conditions 

Fatigue
a
  

 

Mucosal 

inflammation
a 

 

Pyrexia 

Chest pain
a 

 

Pain
a 

 

Asthenia
a 

 

Malaise
e
  

 

Oedema 

peripheral
e
 

Injection site 

reaction 

 

Injury, poisoning 

and procedural 

complications 

 Transfusion 

reaction
e
 

  

a See section: Description of selected adverse reactions  
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section 

Description of selected adverse reactions)  
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck 

pain  
d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC mobilization 
e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the 

underlying malignancy or cytotoxic chemotherapy 

 



 

32 

Description of selected adverse reactions 

 

Hypersensitivity 

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and 

hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in 

post-marketing experience. Overall, reports were more common after intravenous 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.  

 

Pulmonary adverse reactions 

In clinical studies and the post-marketing setting pulmonary adverse reactions 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 

section 4.4). 

 

Splenomegaly and splenic rupture 

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. 

Some cases of splenic rupture were fatal (see section 4.4).   

 

Capillary leak syndrome 

Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor use. 

These have generally occurred in patients with advanced malignant diseases, sepsis, using multiple 

chemotherapy medicinal products or undergoing apheresis (see section 4.4). 

 

Cutaneous vasculitis 

Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitis 

in patients receiving filgrastim is unknown. During long-term use cutaneous vasculitis has been 

reported in 2% of SCN patients. 

 

Leukocytosis 

Leukocytosis (WBC > 50 x 10
9
/L) was observed in 41% of normal donors and transient 

thrombocytopenia (platelets < 100 x 10
9
/L) following filgrastim treatment and leukapheresis was 

observed in 35% of donors (see section 4.4). 

 

Sweets syndrome 

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients 

treated with filgrastim. 

 

Pseudogout (chondrocalcinosis pyrophosphate) 

Pseudogout (chondrocalcinosis pyrophosphate) has been reported in cancer patients treated with 

filgrastim. 

 

GvHD 

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 

marrow transplantation (see sections 4.4 and 5.1). 

 

Paediatric population  

 

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 

similar in both adults, children and adolescents 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.  

 

Other special populations  

 

Elderly 



 

33 

No overall differences in safety or effectiveness were observed between subjects over 65 years of age 

compared to younger adult (>18 years of age) subjects receiving cytotoxic chemotherapy and clinical 

experience has not identified differences in the responses between elderly and younger adult patients. 

There is insufficient data to evaluate filgrastim use in elderly subjects for other approved Grastofil 

indications.  

  

Paediatric SCN patients 

Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe 

chronic neutropenia receiving chronic treatment with filgrastim.  

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

The effects of Grastofil 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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC code: L03AA02 

 

Grastofil is a biosimilar medicinal product. Detailed information is available on the website of the 

European Medicines Agency http://www.ema.europa.eu.  

 

Pharmacodynamic effects 

 

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils 

from the bone marrow. Grastofil containing r-metHuG-CSF (filgrastim) causes marked increases in 

peripheral blood neutrophil counts within 24 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 

peripheral blood. These autologous 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/


 

34 

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 randomised studies, 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.  

 

Relative risk (95% CI) of GvHD and TRM following treatment with G-CSF after bone 

marrow (BM) transplantation 

Publication  Period of 

study 

N Acute grade          

II - IV GvHD 

Chronic 

GvHD 

TRM 

Meta-Analysis   

(2003)  

1986 – 2001
a
 

 1198  1.08 

(0.87, 1.33)  

1.02 

(0.82, 1.26)  

0.70 

(0.38, 1.31)  

European 

Retrospective  

Study (2004)  

1992 – 2002
b
 

 1789  1.33 

    (1.08, 1.64)  

1.29 

(1.02, 1.61)  

1.73 

(1.30, 2.32)  

International 

Retrospective  

Study (2006)  

1995 – 2000
b
 

 2110  1.11 

  (0.86, 1.42)  

1.10 

(0.86, 1.39)  

1.26 

(0.95, 1.67)  

a
 

Analysis includes studies involving BM transplant during this period; some studies used GM-CSF  
b
 

Analysis includes patients receiving BM transplant during this period  

 

Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC 

transplantation  

 

In normal donors, a 10 micrograms/kg/day dose administered subcutaneously for 4 - 5 consecutive 

days allows a collection of ≥ 4 x 10
6 

 

CD34
+
 cells/kg recipient body weight in the majority of the 

donors after two leukaphereses.  

 

Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic 

neutropenia) induces a sustained increase in ANCs 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 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. 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Following subcutaneous administration of recommended doses, serum concentrations were maintained 

above 10 ng/mL for 8 - 16 hours.  

Distribution  

 

The volume of distribution in blood is approximately 150 mL/kg.  



 

35 

 

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 half-lives.  

 

Linearity 

 

There is a positive linear correlation between the dose and the serum concentration of filgrastim, 

whether administered intravenously or subcutaneously.  

 

5.3 Preclinical safety data 

 

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed 

changes attributable to the expected pharmacological actions including increases in leukocytes, 

myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These 

changes all reversed after discontinuation of treatment. 

 

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous  

(80 μg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was 

maternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live 

litter size and fetal weight were observed. 

 

Based on reported data for another filgrastim product similar to Grastofil, comparable findings plus 

increased fetal malformations were observed at 100 μg/kg/day, a maternally toxic dose which 

corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients 

treated with the clinical dose of 5 μg/kg/day. The no observed adverse effect level for embryo-fetal 

toxicity in this study was 10 μg/kg/day, which corresponded to a systemic exposure of approximately 

3-5 times the exposures observed in patients treated with the clinical dose. 

 

In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 μg/kg/day. Offspring of 

rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external 

differentiation and growth retardation (≥20 μg/kg/day) and slightly reduced survival rate  

(100 μg/kg/day).  

 

Filgrastim had no observed effect on the fertility of male or female rats. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Glacial acetic acid  

Sodium hydroxide 

Sorbitol (E420)  

Polysorbate 80 

Water for injections 

 



 

36 

6.2 Incompatibilities 

 

Diluted filgrastim may be adsorbed to glass and plastic materials. 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6.  

 

6.3 Shelf life 

 

3 years. 

 

Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 

24 hours at 2 °C to 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 hours at 2 °C to 8 °C, unless 

dilution has taken place in controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2 °C – 8 °C). Do not freeze.  

Keep the syringe in the outer carton in order to protect from light. 

 

Accidental one-time exposure to freezing temperatures does not adversely affect the stability of 

Grastofil. If exposure has been greater than 24 hours or frozen more than once then Grastofil should 

not be used. 

 

Within its shelf-life and for the purpose of ambulatory use, the patient may remove Grastofil from the 

refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 days. 

At the end of this period, Grastofil should not be put back in the refrigerator and should be disposed of 

in accordance with local requirements. 

 

For storage conditions of the diluted medicinal product, see section 6.3. 

 

6.5 Nature and contents of container  

 

 Type I glass pre-filled syringe with permanently attached stainless steel needle in the tip and 1/40 

printed markings for graduations from 0.1 mL to 1 mL on the barrel. The needle cover of the pre-filled 

syringe contains dry natural rubber (latex, see section 4.4). Each pre-filled syringe contains 0.5 mL 

solution. 

 

Pack sizes: Cartons containing 1 or 5 pre-filled syringes. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

If required, Grastofil may be diluted in 5% glucose solution for injection/infusion. Dilution to a final 

concentration less than 0.2 MU (2 µg) 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. Do not shake.  

 

For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per mL, human 

serum albumin (HSA) should be added to a final concentration of 2 mg/mL. Example: In a final 

injection volume of 20 mL, total doses of filgrastim less than 30 MU (300 µg) should be given with 

0.2 mL of 200 mg/mL (20%) human albumin solution added. 

 



 

37 

Grastofil contains no preservative. In view of the possible risk of microbial contamination, Grastofil 

pre-filled syringes are for single use only. 

 

When diluted in 5% glucose, Grastofil is compatible with glass and a variety of plastics including 

PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 

 

Disposal  

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/877/003 

EU/1/13/877/004 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 18 October 2013 

Date of latest renewal: 4 October 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


 

38 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 

SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 

FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 



 

39 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) of the biological active substance(s) 

 

Intas Pharmaceuticals Limited 

Plot no: 423 P/A 

Sarkhej Bavla Highway  

Moraiya; Taluka: Sanand, 

Ahmedabad – 382213 Gujarat, India 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Apotex Nederland B.V. 

Archimedesweg 2 

2333 CN Leiden  

Netherlands 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2. of the Marketing Authorisation Application and any 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 

 At the request of the European Medicines Agency; 
 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached.  

 



 

40 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

41 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

42 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Grastofil 30 MU/0.5 mL solution for injection/infusion in pre-filled syringe 

filgrastim 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each syringe of 0.5 mL solution contains 30 MU (300 micrograms) of filgrastim  

(600 micrograms/mL). 

 

 

3. LIST OF EXCIPIENTS 

 

Glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injections. See 

leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection/infusion 

1 pre-filled syringe (0.5 mL) 

5 pre-filled syringes (0.5 mL) 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use.  

For single use only. 

Do not shake. 

Subcutaneous and intravenous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP: 

 

A diluted solution of Grastofil for infusion should be used within 24 hours when stored at  

2 °C to 8 °C. 

 



 

43 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Do not freeze. 

Keep the syringe in the outer carton in order to protect from light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE  

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/877/001 1 prefilled syringe 

EU/1/13/877/002 5 prefilled syringes 

 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Grastofil 30 MU/0.5 mL 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 

PC:  

SN:  
NN:  

 

 



 

44 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  

 

PRE-FILLED SYRINGE 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Grastofil 30 MU/0.5 mL solution for injection/infusion in pre-filled syringe   

filgrastim  

SC/IV 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

0.5 mL 

 

 

6. OTHER 

 

 



 

45 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Grastofil 48 MU/0.5 mL solution for injection/infusion in pre-filled syringe   

filgrastim 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each syringe of 0.5 mL solution contains 48 MU (480 micrograms) of filgrastim  

(960 micrograms/mL). 

 

 

3. LIST OF EXCIPIENTS 

 

Glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injections. See 

leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection/infusion 

1 pre-filled syringe (0.5 mL) 

5 pre-filled syringes (0.5 mL) 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use.  

For single use only. 

Do not shake. 

Subcutaneous and intravenous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Do not freeze. 



 

46 

Keep the syringe in the outer carton in order to protect from light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE  

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/877/003 1 prefilled syringe 

EU/1/13/877/004 5 prefilled syringes 

 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Grastofil 48 MU/0.5 mL 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 

PC:  

SN:  
NN:  

 



 

47 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  

 

PRE-FILLED SYRINGE 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Grastofil 48 MU/0.5 mL solution for injection/infusion in pre-filled syringe   

filgrastim  

SC/IV 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

0.5 mL 

 

 

6. OTHER 

 

 



 

48 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

49 

PACKAGE LEAFLET: INFORMATION FOR THE USER 

 

Grastofil 30 MU/0.5 mL solution for injection/infusion in pre-filled syringe 

filgrastim 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
 

 Keep this leaflet. You may need to read it again. 

 If you have any further questions, ask your doctor, pharmacist or nurse. 

 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

In this leaflet 

 

1. What Grastofil is and what it is used for 

2. What you need to know before you use Grastofil 

3. How to use Grastofil 

4. Possible side effects 

5. How to store Grastofil 

6. Contents of the pack and other information 

 

 

1. What Grastofil is and what it is used for 

 

What Grastofil is 

Grastofil contains the active substance filgrastim. Grastofil is a white blood cell growth factor 

(granulocyte colony stimulating factor) and belongs to a group of medicines called cytokines. Growth 

factors are proteins that are produced naturally in the body but they can also be made using 

biotechnology for use as a medicine. Grastofil works by stimulating the bone marrow to produce more 

white blood cells.  

 

A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes 

your body less able to fight infection. Filgrastim stimulates the bone marrow (the tissue where new 

blood cells are made) to produce more white blood cells that help fight infection.  

 

What Grastofil is used for 

Your doctor has prescribed Grastofil,  which is used to treat neutropenia (nu-tro-peen-ee-ah), a 

condition where the body makes too few neutrophils. Neutropenia may be a long-standing condition 

where your body does not make enough neutrophils, or it may be caused by drugs used to treat cancer. 

In some cases, your body may make enough neutrophils, but as a part of your treatment for cancer, 

your doctor may want to increase the number of certain blood cells (CD34 cells) and collect them. The 

cells are collected using a process called apheresis (ay-fer-ree-sis). These collected cells are given 

back to you after you receive very high doses of treatment for cancer to make your blood counts get 

back to normal more quickly. Your doctor will tell you why you are being treated with Grastofil.  

 



 

50 

Grastofil can be used: 

 

 to increase the number of white blood cells after treatment with chemotherapy to help prevent 
infections; 

 to increase the number of white blood cells after a bone marrow transplant to help prevent 
infections; 

 to increase the number of white blood cells if you suffer from severe chronic neutropenia to help 
prevent infections; 

 in patients with advanced HIV infection which will help reduce the risk of infections;  

 before high-dose chemotherapy to make the bone marrow produce more stem cells which can be 
collected and given back to you after your treatment. These can be taken from you or from a 

donor. The stem cells will then go back into the bone marrow and produce blood cells.  

 

 

2. What you need to know before you use Grastofil 

 

Do not use Grastofil 

 if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in section 
6). 

 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Grastofil. 

 

Please tell your doctor before starting treatment if you have: 

   

 osteoporosis (bone disease), 

 sickle cell anaemia, as filgrastim may cause sickle cell crisis. 
 

Please tell your doctor immediately during treatment with Grastofil, if you:  

 

 have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, 
tongue or other parts of the body, shortness of breath, wheezing or trouble breathing as these 

could be signs of a severe allergic reaction (hypersensitivity). 

 experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you 
notice you urinate less than usual (glomerulonephritis). 

 get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left 
shoulder (these may be symptoms of an enlarged spleen (splenomegaly), or possibly rupture of 

the spleen).  

 notice unusual bleeding or bruising (these may be symptoms of a decrease in blood platelets 
(thrombocytopenia), with a reduced ability of your blood to clot). 

Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) 

has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, 

abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you 

experience these symptoms.  

Loss of response to filgrastim 

If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 

doctor will investigate the reasons why including whether you have developed antibodies which 

neutralise filgrastim’s activity. 

 

Your doctor may want to monitor you closely, see section 4 of the package leaflet. 

 

If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the 

blood (leukaemia, myelodysplastic syndrome (MDS)). You should talk to your doctor about your risks 



 

51 

of developing cancers of the blood and what testing should be done. If you develop or are likely to 

develop cancers of the blood, you should not use Grastofil, unless instructed by your doctor. 

 

If you are a stem cell donor, you must be aged between16 and 60 years. 

 

Take special care with other medicines that stimulate white blood cells 
Grastofil is one of a group of medicines that stimulate the production of white blood cells. Your 

healthcare professional should always record the exact medicine you are using. 

 

Other medicines and Grastofil 
You should not receive Grastofil in the 24 hours before and the 24 hours after receiving 

chemotherapy. 

 

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 

 

Pregnancy and breast-feeding 
Grastofil has not been tested in pregnant or breast-feeding women.  

 

It is important to tell your doctor if you: 

 are pregnant; or breast-feeding; 

 think you may be pregnant, or 

 are planning to have a baby. 
 

If you become pregnant during Grastofil treatment, please inform your doctor. 

 

Unless your doctor directs you otherwise, you must stop breast-feeding if you use Grastofil.  

 

Driving and using machines 
Grastofil may have a minor influence on your ability to drive and use machines. This medicine may 

cause dizziness. It is advisable to wait and see how you feel after receiving Grastofil and before 

driving or operating machinery. 

 

Grastofil contains sorbitol 

Grastofil contains 50 mg sorbitol in each ml.  

Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare 

genetic disorder, you (or your child) must not receive this medicine. Patients with HFI cannot break 

down fructose, which may cause serious side effects. 

 

You must tell your doctor before receiving this medicine if you (or your child) have HFI or if your 

child can no longer take sweet foods or drinks because they feel sick, vomit or get unpleasant effects 

such as bloating, stomach cramps or diarrhoea. 

 

Grastofil contains sodium 

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-

free’.  

 

Grastofil pre-filled syringe contains dry natural rubber 

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may 

cause an allergic reaction. 

 

3. How to use Grastofil 

 

Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or 

pharmacist if you are not sure. 

 

The usual dose of Grastofil varies depending on your illness and weight. Your doctor will tell you how 

much Grastofil you should take.  



 

52 

Dose 

 

Grastofil and neutropenia (low number of a type of white blood cells) associated with chemotherapy  

 

The usual dose is 0.5 million units (5 micrograms) per kilogram of bodyweight each day. For example, 

if you weigh 60 kilograms your daily dose will be 30 million units (300 micrograms). Your treatment 

with Grastofil will usually last for about 14 days. In some disease types, however, longer treatment 

lasting up to about one month may be required. 

 

Grastofil and bone marrow transplantation  

 

The usual starting dose is 1 million units (10 micrograms) per kilogram of bodyweight each day given 

as an infusion. For example, if you weigh 60 kilograms your daily dose will be 60 million units (600 

micrograms). You will normally receive your first dose of Grastofil at least 24 hours after your 

chemotherapy and at least 24 hours after receiving your bone marrow transplant. Your doctor may 

then test your blood to see how well the treatment is working and how long it should last. 

 

Grastofil and severe chronic neutropenia (low number of a type of white blood cells)  

 

The usual starting dose is between 0.5 million units  (5 micrograms) and 1.2 million units (12 

micrograms) per kilogram bodyweight each day in a single or divided dose. Your doctor may then test 

your blood to see how well your treatment with Grastofil is working and to find the dose that is best 

for you. Long-term treatment with Grastofil is required for reduction in neutropenia. 

 

Grastofil and neutropenia (low number of a type of white blood cells) in patients with HIV infection  

 

The usual starting dose is between 0.1 million units (1 micrograms) and 0.4 million units (4 

micrograms) per kilogram bodyweight each day. Your doctor may test your blood at regular intervals 

to see how well the Grastofil treatment is working. Once the number of white cells in your blood has 

returned to normal it may be possible to reduce the dose frequency to less than once per day. Long 

term treatment with Grastofil may be required to maintain a normal number of white cells in your 

blood.  

 

Grastofil and peripheral blood stem cell transplantation (stem cells collected from the blood to use in 

bone marrow transplantation) 

 

If you are donating stem cells for yourself, the usual dose is 0.5 million units (5 micrograms) to 1 

million units (10 micrograms) per kilogram bodyweight each day. Grastofil treatment will last for up 

to 2 weeks. Your doctor will monitor your blood to determine the best time to collect the stem cells.  

 

If you are acting as a stem cell donor for another person, the usual dose is 1 million units (10 

micrograms) per kilogram bodyweight each day. Grastofil treatment will last for 4 to 5 days. Your 

doctor will perform regular blood tests to determine the best time to collect the stem cells. 

 

How Grastofil is given 
 

Grastofil  is usually given as a daily injection  into the tissue just under the skin (known as a 

subcutaneous injection). It can also be given as a daily slow injection into the vein (known as an 

intravenous infusion).  

 

If you are receiving this medicine by subcutaneous injection, your doctor may suggest that you learn 

how to give yourself the injections. Your doctor or nurse will give you instructions on how to do this 

(see information below on instructions for injecting Grastofil). Do not attempt to self-administer 

without this training. Some of the information you require is given at the end of this leaflet, but proper 

treatment of your disease requires close and constant co-operation with your doctor. 

 



 

53 

How long will I have to take Grastofil? 

 

You will need to take Grastofil until your white blood cell count is normal. Regular blood tests will 

be taken to monitor the number of white blood cells in your body. Your doctor will tell you how long 

you will need to take Grastofil. 

 

Use in children and adolescents 
 

Grastofil is used to treat children and adolescents who are receiving chemotherapy or who suffer from 

severe low white blood cell count (neutropenia). The dosing in children and adolescents receiving 

chemotherapy is the same as for adults. 

 

Instructions for injecting Grastofil 
 

This section contains information on how to give yourself an injection of Grastofil.  

 

Important: do not try to give yourself an injection unless you have received training from your doctor 

or nurse.  

 

Grastofil is injected into the tissue just under the skin. This is known as a subcutaneuous injection. 

 

Equipment that you need 

 

To give yourself a subcutaneous injection you will need:  

 a new pre-filled syringe of Grastofil; and  

 alcohol wipes or similar.  

 

What should I do before I give myself a subcutaneous injection of Grastofil?  

 

1. Remove the syringe from the refrigerator. Leave the syringe at room temperature  
(15ºC to 25 ºC)  for approximately 30 minutes or hold the pre-filled syringe gently in your hand 

for a few minutes. This will make the injection more comfortable. Do not warm Grastofil in any 

other way (for example, do not warm it in a microwave or in hot water). 

2. Do not shake the pre-filled syringe. 
3. Do not remove the needle cover until you are ready to inject. 
4. Wash your hands thoroughly. 
5. Find a comfortable, well-lit, clean surface and put all the equipment you need within reach. 

 

How do I prepare my Grastofil injection?  

 

Before you inject Grastofil you must do the following:  

1. To avoid bending the needle, gently pull the cover from the needle without twisting. 
2. Do not touch the needle or push the plunger.  
3. You may notice a small air bubble in the pre-filled syringe. You do not need to remove the air 

bubble before injecting. Injecting the solution with the air bubble is harmless.   

4. The Grastofil syringe has a scale on the syringe barrel. Hold the syringe with the needle pointing 
up. Push the plunger up slowly to the number (given in mL) that matches the dose of Grastofil 

which your doctor has prescribed. 

5. You can now use the pre-filed syringe, 

 

Where should I give my injection?  

 

The best places to inject are the top of the thighs and the abdomen. If someone else is injecting you, 

they can also use the back of your arms. 

 

You may change the injection site if you notice the area is red or sore. 

 



 

54 

      
 

How do I give my injection?  

 

1. Disinfect your skin by using an alcohol wipe and pinch (without squeezing) the skin between 
your thumb and forefinger.  

2. Put the needle fully into the skin as shown by your nurse or doctor.  
3. Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see blood 

in the syringe, pull the needle out and re-insert it in another place.  

4. Push the plunger with a slow constant pressure, always keeping your skin pinched, until the 
syringe is empty. 

5. Remove the needle and let go of your skin. Do not put the cover back on used needles, as you 
may accidentally prick yourself. 

6. If you notice a spot of blood you may gently dab it away with a cotton ball or tissue. Do not rub 
the injection site. If needed, you may cover the injection site with a plaster.  

7. Only use each syringe for one injection. Do not use any Grastofil that may be left in the syringe. 
 

  
 

Remember:  if you have any problems, please ask your doctor or nurse for help and advice.  

 

If you use more Grastofil than you should 
 

If you use more Grastofil than you should, contact your doctor or pharmacist as soon as possible. 

 

If you forget to use Grastofil 

 

If you have missed an injection, contact your doctor as soon as possible. 

 

Do not take a double dose to make up for a forgotten injection. Contact your doctor to discuss when 

you should inject the next dose. 



 

55 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Tell your doctor immediately during treatment if: 

 

 you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the 

face, lips, mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea).  

 you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of Acute 
Respiratory Distress Syndrome (ARDS).  

   you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients who 

received filgrastim. Call your doctor right away if you experience puffiness in your face or 

ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual. 

 you have any of the following or a combination of the following side effects:  
o swelling or puffiness, which may be associated with passing water less frequently, 

difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling 

of tiredness. These symptoms generally develop in a rapid fashion.  

These could be symptoms of a condition called “Capillary Leak Syndrome” which causes blood 

to leak from the small blood vessels into your body and needs urgent medical attention.  

 you have a combination of any of the following symptoms: 
o fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, 

shortness of breath, extreme pain or discomfort and clammy or sweaty skin. 

These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 

severe infection with whole-body inflammatory response which can be life threatening and 

needs urgent medical attention. 

 you get left upper belly (abdominal) pain, pain below the left rib cage or pain at the tip of your 
shoulder, as there may be a problem with your spleen (enlargement of the spleen (splenomegaly) 

or rupture of the spleen). 

 you are being treated for severe chronic neutropenia and you have blood in your urine 
(haematuria). Your doctor may regularly test your urine if you experience this side effect or if 

protein is found in your urine (proteinuria). 

 

A common side effect of Grastofil use is pain in your muscles or bones (musculoskeletal pain), which 

can be helped by taking standard pain relief medicines (analgesics). In patients undergoing a stem cell 

or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of the 

donor cells against the patient receiving the transplant; signs and symptoms include rash on the palms 

of your hands or soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your eyes, 

lungs, vagina and joints.  

 

In normal stem cell donors an increase in white blood cells (leukocytosis) and a decrease of platelets 

may be seen, this reduces the ability of your blood to clot (thrombocytopenia), these will be monitored 

by your doctor. 

 

Very common side effects (may affect more than 1 in 10 people): 

 decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 

 low red blood cell count (anaemia) 

 headache 

 diarrhoea 

 vomiting 

 nausea 

 unusual hair loss or thinning (alopecia) 



 

56 

 tiredness (fatigue) 

 soreness and swelling of the digestive tract lining which runs from the mouth to the anus 
(mucosal inflammation) 

 fever (pyrexia) 

 

Common side effects (may affect up to 1 in 10 people):  

 inflammation of the lung (bronchitis) 

 upper respiratory tract infection 

 urinary tract infection 

 decreased appetite 

 trouble sleeping (insomnia) 

 dizziness 

 decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 

 tingling or numbness of the hands or feet (paraesthesia) 

 low blood pressure (hypotension) 

 high blood pressure (hypertension) 

 cough 

 coughing up blood (haemoptysis)  

 pain in your mouth and throat (oropharyngeal pain) 

 nose bleeds (epistaxis) 

 constipation 

 oral pain 

 enlargement of the liver (hepatomegaly) 

 rash 

 redness of the skin (erythema) 

 muscle spasm 

 pain when passing urine (dysuria) 

 chest pain 

 pain 

 generalised weakness (asthenia) 

 generally feeling unwell (malaise) 

 swelling in the hands and feet (oedema peripheral) 

 increase of certain enzymes in the blood 

 changes in blood chemistry 

 transfusion reaction 

 

Uncommon side effects (may affect up to 1 in 100 people):  

 increase in white blood cells (leukocytosis) 

 allergic reaction (hypersensitivity) 

 rejection of transplanted bone marrow (graft versus host disease) 

 high uric acid levels in the blood, which may cause gout (hyperuricaemia) (Blood uric acid 
increased) 

 liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 

 lungs do not function as they should, causing breathlessness (respiratory failure) 

 swelling and/or fluid in the lungs (pulmonary oedema) 

 inflammation of the lungs (interstitial lung disease) 

 abnormal x-rays of the lungs (lung infiltration) 

 bleeding from the lung (pulmonary haemorrhage) 

 lack of absorption of oxygen in the lung (hypoxia) 

 bumpy skin rash (rash macuo-papular) 

 disease which causes bones to become less dense, making them weaker, more brittle and likely 
to break (osteoporosis) 

 injection site reaction 
 



 

57 

Rare side effects (may affect up to 1 in 1,000 people): 

 severe pain in the bones, chest, gut or joints (sickle cell anaemia with crisis) 

 sudden life-threatening allergic reaction (anaphylactic reaction) 

 pain and swelling of the joints, similar to gout (pseudogout) 

 a change in how your body regulates fluids within your body and may result in puffiness (fluid 
volume disturbances) 

 inflammation of the blood vessels in the skin (cutaneous vasculitis) 

 plum-coloured, raised, painful sores on the limbs and sometimes the face and neck with a fever 
(Sweets syndrome) 

 worsening of rheumatoid arthritis 

 unusual change in the urine 

 bone density decreased 

 Inflammation of the aorta (the large blood vessel which transports blood from the heart to the 
body), see section 2. 

 

Reporting of side effects  

 

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V By reporting side effects you can help provide more information on the safety of this 

medicine.  

 

 

5. How to store Grastofil 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the outer carton and on the pre-filled 

syringe after EXP. The expiry date refers to the last day of the month. 

 

Store in a refrigerator (2°C - 8°C). Do not freeze. 

 

Keep the pre-filled syringe in the carton in order to protect from light. 

 

Grastofil can be removed from the refrigerator and left at room temperature (not above 25℃) for a 
single period of up to 15 days that ends within the labelled expiry date. Once Grastofil has been out at 

room temperature it should not be put back into the refrigerator. Any Grastofil syringes that have been 

out of the refrigerator for longer than 15 days should not be used and should be disposed of in 

accordance with local requirements. 

 

Do not use Grastofil if you notice it is cloudy, or there is discoloration or there are particles in it. 

 

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 

dispose of medicines no longer required. These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Grastofil contains  

 

 The active substance is filgrastim. Each mL of solution contains 60 million units (MU) 
(equivalent to 600 micrograms [μg]) of filgrastim. Each pre-filled syringe contains 30 MU 

(300 μg) filgrastim in 0.5 mL solution. 

 The other ingredients are glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80 
and water for injections. See section 2 “What you need to know before you use Grastofil”. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

58 

What Grastofil looks like and contents of the pack 
 

Grastofil is a clear colourless solution for injection or infusion. It is supplied in a pre-filled syringe 

with an injection needle marked with 1/40 printed markings from 0.1 mL to 1 mL on the syringe 

barrel. Each pre-filled syringe contains 0.5 mL of solution. 

 

Grastofil is available in packs containing 1 and 5 pre-filled syringes.  

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain                                                                                                                                 

 

Manufacturer 
 

Apotex Nederland B.V. 

Archimedesweg 2 

2333 CN Leiden  

Netherlands 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Eurogenerics SA/NV                                   

Telephone +32/2.479.78.78 

Lietuva                                                               

STADA Arzneimittel AG                                             

Telephone +49/6101.603.0 

 

България 

STADA Arzneimittel AG                                

Telephone +49/6101.603.0 

 

Luxembourg/Luxemburg 
Eurogenerics SA/NV 

Telephone +32/2.479.78.78 

 

Česká republika 
STADA Pharma CZ s.r.o.                                

Telephone +420/257-888.111 

 

Magyarország                                         

STADA Arzneimittel AG                                 

Telephone +49/6101.603.0  

 

Danmark 
STADA Nordic ApS                                      

Telephone +45/44.85.99.99 

 

Malta 
PharmaMt Ltd. 

Telephone +356/21337008 

 

Deutschland 
STADAPHARM GmbH 

Telephone +49/6101.603.0 

Nederland 
Centrafarm BV                                                

Telephone +31/7650.81.000 

 

Eesti 

STADA Arzneimittel AG                              

Telephone +49/6101.603.0 

 

Norge 
STADA Arzneimittel AG                                            

Telephone +49/6101.603.0 

 

Ελλάδα 
Rafarm AEBE 

Κορίνθου 12, Ν. Ψυχικό, 15451, Αθήνα 

Telephone +30/2106776550  

 

Österreich 
STADA Arzneimittel Gesellschaft m.b.H.                                    

Telephone +43/1-367.85.85.0 



 

59 

 

España 
Laboratorio STADA S.L. 

Telephone +34/93-473.88.89 

Polska 
STADA Poland Sp. z.oo.                                                        

Telephone +48/22 -737.79.20  

 

France 

EG LABO-Laboratoires Eurogenerics SAS  

Telephone +33/1-46.94.86.86 

 

Portugal                                                                        
Apotex Europe B.V.                                           

Telephone +(31) 71. 565.77.77  

 

Hrvatska 

STADA d.o.o                                                         

Telephone +385/1.3764.111 

 

România 

STADA Arzneimittel AG                                

Telephone +49/6101.603.0 

 

Ireland 
CLONMEL Healthcare Ltd. 

Telephone +353/52.61.77.777 

 

Slovenija                                                                       
STADA d.o.o.                                                      

Telephone +386/1-589.67.10 

 

Ísland 

STADA Arzneimittel AG  

Telephone +49/6101.603.0 

 

Slovenská republika 
STADA PHARMA Slovakia s.r.o. 

Telephone +421/2-5262.1933 

 

Italia 
CRINOS S.p.A.  

Telephone +39/02-89.421721 

 

Suomi/Finland                                                             

STADA Nordic ApS, Suomen sivuliike                                       

Telephone +358/207.416.888 

 

Κύπρος 

STADA Arzneimittel AG                                          

Telephone +49/6101.603.0 

 

Sverige                                                     

STADA Nordic ApS                                                   

Telephone +45/44.85.99.99 

 

Latvija                                                             

STADA Arzneimittel AG                                             

Telephone +49/6101.603.0 

 

United Kingdom 

Thornton & Ross Ltd. 

Telephone +44/1484-842.217  

 

This leaflet was last revised in MM/YYYY 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu  

 

--------------------------------------------------------------------------------------------------------------- 

 

The following information is intended for medical or healthcare professionals only:  
 

In order to improve the traceability of biological medicinal products, the name and the batch number 

of the administered product should be clearly recorded.  

 

If required, Grastofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 

(2 µg) 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 MU (15 µg) per mL, human 

serum albumin (HSA) should be added to a final concentration of 2 mg/mL. Example: In a final 

injection volume of 20 mL, total doses of filgrastim less than 30 MU (300 µg) should be given with 

0.2 mL of 200 mg/mL (20%) human albumin solution added. 

http://www.ema.europa.eu/


 

60 

When diluted in 5% glucose, Grastofil is compatible with glass and a variety of plastics including 

PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 

 



 

61 

PACKAGE LEAFLET: INFORMATION FOR THE USER 

 

Grastofil 48 MU/0.5 mL solution for injection/infusion in pre-filled syringe 

filgrastim 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
 

 Keep this leaflet. You may need to read it again. 

 If you have any further questions, ask your doctor, pharmacist or nurse. 

 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

In this leaflet 

 

1. What Grastofil is and what it is used for 

2. What you need to know before you use Grastofil 

3. How to use Grastofil 

4. Possible side effects 

5. How to store Grastofil 

6. Contents of the pack and other information 

 

 

1. What Grastofil is and what it is used for 

 

What Grastofil is 

  

Grastofil contains the active substance filgrastim. Grastofil is a white blood cell growth factor 

(granulocyte colony stimulating factor) and belongs to a group of medicines called cytokines. Growth 

factors are proteins that are produced naturally in the body but they can also be made using 

biotechnology for use as a medicine. Grastofil works by stimulating the bone marrow to produce more 

white blood cells.  

 

A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes 

your body less able to fight infection.  Filgrastim stimulates the bone marrow (the tissue where new 

blood cells are made) to produce more white blood cells that help fight infection.  

 

What Grastofil is used for 

 

Your doctor has prescribed Grastofil, which is used to treat neutropenia (nu-tro-peen-ee-ah), a 

condition where the body makes too few neutrophils. Neutropenia may be a long-standing condition 

where your body does not make enough neutrophils, or it may be caused by drugs used to treat cancer. 

In some cases, your body may make enough neutrophils, but as a part of your treatment for cancer, 

your doctor may want to increase the number of certain blood cells (CD34 cells) and collect them. The 

cells are collected using a process called apheresis (ay-fer-ree-sis). These collected cells are given 

back to you after you receive very high doses of treatment for cancer to make your blood counts get 

back to normal more quickly. Your doctor will tell you why you are being treated with Grastofil.  

 



 

62 

Grastofil can be used:  

 

 to increase the number of white blood cells after treatment with chemotherapy to help prevent 
infections;  

 to increase the number of white blood cells after a bone marrow transplant to help prevent 
infections 

 to increase the number of white blood cells if you suffer from severe chronic neutropenia to help 
prevent infections;  

 in patients with advanced HIV infection which will help reduce the risk of infections;   

 before high-dose chemotherapy to make the bone marrow produce more stem cells which can be 
collected and given back to you after your treatment. These can be taken from you or from a 

donor. The stem cells will then go back into the bone marrow and produce blood cells. 

 

 

2. What you need to know before you use Grastofil 

 

Do not use Grastofil 

 

 if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in section 
6). 

 

Warnings and precautions 

 

Talk to your doctor, pharmacist or nurse before using Grastofil: 

 

Please tell your doctor before starting treatment if you have: 

 

 osteoporosis (bone disease),  

 sickle cell anaemia, as filgrastim can cause sickle cell crisis. 
 

Please tell your doctor immediately during treatment with Grastofil, if you:  

 

 have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, 
tongue or other parts of the body, shortness of breath, wheezing or trouble breathing as these 

could be signs of a severe allergic reaction (hypersensitivity). 

 experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you 
notice you urinate less than usual (glomerulonephritis). 

 get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left 
shoulder (these may be symptoms of an enlarged spleen (splenomegaly), or possibly rupture of 

the spleen).  

 notice unusual bleeding or bruising (these may be symptoms of a decrease in blood platelets 
(thrombocytopenia), with a reduced ability of your blood to clot). 

Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) 

has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, 

abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you 

experience these symptoms. 

 

Loss of response to filgrastim 

 

If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 

doctor will investigate the reasons why including whether you have developed antibodies which 

neutralise filgrastim’s activity 

 

Your doctor may want to monitor you closely, see section 4 of the package leaflet. 

 



 

63 

If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the 

blood (leukaemia, myelodysplastic syndrome (MDS)). You should talk to your doctor about your risks 

of developing cancers of the blood and what testing should be done. If you develop or are likely to 

develop cancers of the blood, you should not use Grastofil, unless instructed by your doctor. 

 

If you are a stem cell donor, you must be aged between16 and 60 years. 

   

Take special care with other medicines that stimulate white blood cells 

 

Grastofil is one of a group of medicines that stimulate the production of white blood cells. Your 

healthcare professional should always record the exact medicine you are using. 

 

Other medicines and Grastofil 
 

You should not receive Grastofil in the 24 hours before and the 24 hours after receiving 

chemotherapy. 

 

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 

 

Pregnancy and breast-feeding 

 

Grastofil has not been tested in pregnant or breast-feeding women.  

 

It is important to tell your doctor if you  

 are pregnant, or breast-feeding; 

 think you may be pregnant, or  

 plan to have a baby. 
 

If you become pregnant during Grastofil treatment, please inform your doctor. 

 

Unless your doctor directs you otherwise, you must stop breast-feeding if you use Grastofil.  

 

 

Driving and using machines 
 

Grastofil may have a minor influence on your ability to drive and use machines. This medicine may 

cause dizziness. It is advisable to wait and see how you feel after receiving Grastofil and before 

driving or operating machinery. 

 

Grastofil contains sorbitol 

 

Grastofil contains 50 mg sorbitol in each ml. Sorbitol is a source of fructose. If you (or your child) 

have hereditary fructose intolerance (HFI), a rare genetic disorder, you (or your child) must not 

receive this medicine. Patients with HFI cannot break down fructose, which may cause serious side 

effects. 

 

You must tell your doctor before receiving this medicine if you (or your child) have HFI or if your 

child can no longer take sweet foods or drinks because they feel sick, vomit or get unpleasant effects 

such as bloating, stomach cramps or diarrhoea. 

 

Grastofil contains sodium 

 

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-

free’.  

 



 

64 

Grastofil pre-filled syringe contains dry natural rubber 

 

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may 

cause an allergic reaction. 

 

 

3. How to use Grastofil 

 

Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or 

pharmacist if you are not sure. 

 

The usual dose of Grastofil varies depending on your illness and weight. Your doctor will tell you how 

much Grastofil you should take. 

   

Dose 

 

Grastofil and neutropenia (low number of a type of white blood cells) associated with chemotherapy  

 

The usual dose is 0.5 million units (5 micrograms) per kilogram of bodyweight each day. For example, 

if you weigh 60 kilograms your daily dose will be 30 million units (300 micrograms). Your treatment 

with Grastofil will usually last for about 14 days. In some disease types, however, longer treatment 

lasting up to about one month may be required. 

 

Grastofil and bone marrow transplantation  

 

The usual starting dose is 1 million units (10 micrograms) per kilogram of bodyweight each day given 

as an infusion. For example, if you weigh 60 kilograms your daily dose will be 60 million units (600 

micrograms). You will normally receive your first dose of Grastofil at least 24 hours after your 

chemotherapy and at least 24 hours after receiving your bone marrow transplant. Your doctor may 

then test your blood to see how well the treatment is working and how long it should last. 

 

Grastofil and severe chronic neutropenia (low number of a type of white blood cells)  

 

The usual starting dose is between 0.5 million units  (5 micrograms) and 1.2 million units (12 

micrograms) per kilogram bodyweight each day in a single or divided dose. Your doctor may then test 

your blood to see how well your treatment with Grastofil is working and to find the dose that is best 

for you. Long-term treatment with Grastofil is required for reduction in neutropenia. 

 

Grastofil and neutropenia (low number of a type of white blood cells) in patients with HIV infection  

 

The usual starting dose is between 0.1 million units (1 micrograms) and 0.4 million units (4 

micrograms) per kilogram bodyweight each day. Your doctor may test your blood at regular intervals 

to see how well the Grastofil treatment is working. Once the number of white cells in your blood has 

returned to normal it may be possible to reduce the dose frequency to less than once per day. Long 

term treatment with Grastofil may be required to maintain a normal number of white cells in your 

blood.  

 



 

65 

Grastofil and peripheral blood stem cell transplantation (stem cells collected from the blood to use in 

bone marrow transplantation) 

 

If you are donating stem cells for yourself, the usual dose is 0.5 million units (5 micrograms) to 1 

million units (10 micrograms) per kilogram bodyweight each day. Grastofil treatment will last for up 

to 2 weeks. Your doctor will monitor your blood to determine the best time to collect the stem cells.  

 

If you are acting as a stem cell donor for another person, the usual dose is 1 million units (10 

micrograms) per kilogram bodyweight each day. Grastofil treatment will last for 4 to 5 days. Your 

doctor will perform regular blood tests to determine the best time to collect the stem cells. 

 

How Grastofil is given  
 

Grastofil is usually given as a daily injection into the tissue just under the skin (known as a 

subcutaneous injection). It can also be given as a daily slow injection into the vein (known as an 

intravenous infusion).  

 

If you are receiving this medicine by subcutaneous injection, your doctor may suggest that you learn 

how to give yourself the injections. Your doctor or nurse will give you instructions on how to do this 

(see information below on instructions for injecting Grastofil). Do not attempt to self-administer 

without this training. Some of the information you require is given at the end of this leaflet, but proper 

treatment of your disease requires close and constant co-operation with your doctor. 

 

How long will I have to take Grastofil? 

 

You will need to take Grastofil until your white blood cell count is normal. Regular blood tests will 

be taken to monitor the number of white blood cells in your body. Your doctor will tell you how long 

you will need to take Grastofil. 

 

Use in children and adolescents 

 

Grastofil is used to treat children and adolescents who are receiving chemotherapy or who suffer from 

severe low 

white blood cell count (neutropenia). The dosing in children and adolescents receiving chemotherapy 

is the same as 

for adults. 

 

Instructions for injecting Grastofil 

 

This section contains information on how to give yourself an injection of Grastofil.  

 

Important: do not try to give yourself an injection unless you have received training from your doctor 

or nurse.  

 

Grastofil is injected into the tissue just under the skin. This is known as a subcutaneuous injection. 

 

Equipment that you need  

 

To give yourself a subcutaneous injection you will need:  

 a new pre-filled syringe of Grastofil; and  

 alcohol wipes or similar.  

 

What should I do before I give myself a subcutaneous injection of Grastofil?  

 

1. Remove the syringe from the refrigerator. Leave the syringe at room temperature (15ºC to 25 
ºC) for approximately 30 minutes or hold the pre-filled syringe gently in your hand for a few 



 

66 

minutes. This will make the injection more comfortable. Do not warm Grastofil in any other 

way (for example, do not warm it in a microwave or in hot water). 

2. Do not shake the pre-filled syringe. 
3. Do not remove the needle cover until you are ready to inject. 
4. Wash your hands thoroughly. 
5. Find a comfortable, well-lit, clean surface and put all the equipment you need within reach. 
 

How do I prepare my Grastofil injection?  

 

Before you inject Grastofil you must do the following:  

1. To avoid bending the needle, gently pull the cover from the needle without twisting. 
2. Do not touch the needle or push the plunger.  
3. You may notice a small air bubble in the pre-filled syringe. You do not need to remove the air 

bubble before injecting. Injecting the solution with the air bubble is harmless.  

4. The Grastofil syringe has a scale on the syringe barrel. Hold the syringe with the needle pointing 
up. Push the plunger up slowly to the number (given in mL) that matches the dose of Grastofil 

which your doctor has prescribed. 

5. You can now use the pre-filled syringe. 

 

Where should I give my injection?  

 

The best places to inject are the top of the thighs and the abdomen. If someone else is injecting you, 

they can also use the back of your arms. 

 

You may change the injection site if you notice the area is red or sore. 

 

       
 

How do I give my injection?  

 

1. Disinfect your skin by using an alcohol wipe and pinch (without squeezing) the skin between 
your thumb and forefinger.  

2. Put the needle fully into the skin as shown by your nurse or doctor.  
3. Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see blood 

in the syringe, pull the needle out and re-insert it in another place.  

4. Push the plunger with a slow constant pressure, always keeping your skin pinched, until the 
syringe is empty. 

5. Remove the needle and let go of your skin. Do not put the cover back on used needles, as you 
may accidentally prick yourself. 

6. If you notice a spot of blood you may gently dab it away with a cotton ball or tissue. Do not rub 
the injection site. If needed, you may cover the injection site with a plaster.  

7. Only use each syringe for one injection. Do not use any Grastofil that may be left in the syringe. 
 



 

67 

  
 

Remember:  if you have any problems, please ask your doctor or nurse for help and advice.  

 

If you use more Grastofil than you should 
 

If you use more Grastofil than you should, contact your doctor or pharmacist as soon as possible. 

 

If you forget to use Grastofil 

 

If you have missed an injection, contact your doctor as soon as possible. 

 

Do not take a double dose to make up for a forgotten injection. Contact your doctor to discuss when 

you should inject the next dose. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Tell your doctor immediately during treatment if: 

 

 you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the 

face, lips, mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea).  

 you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of Acute 
Respiratory Distress Syndrome (ARDS).  

 you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients who 
received filgrastim. Call your doctor right away if you experience puffiness in your face or 

ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual. 

 you have any of the following or a combination of the following side effects:  
o swelling or puffiness, which may be associated with passing water less frequently, 

difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling 

of tiredness. These symptoms generally develop in a rapid fashion.  

These could be symptoms of a condition called “Capillary Leak Syndrome” which causes the 

blood to leak from the small blood vessels into your body and needs urgent medical attention.  

 you have a combination of any of the following symptoms: 
o fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, 

shortness of breath, extreme pain or discomfort and clammy or sweaty skin. 

These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 

severe infection with whole-body inflammatory response which can be life threatening and 

needs urgent medical attention. 



 

68 

 you get left upper belly (abdominal) pain, pain below the left rib cage or pain at the tip of your 
shoulder, as there may be a problem with your spleen (enlargement of the spleen (splenomegaly) 

or rupture of the spleen). 

 you are being treated for severe chronic neutropenia and you have blood in your urine 
(haematuria). Your doctor may regularly test your urine if you experience this side effect or if 

protein is found in your urine (proteinuria). 

 

A common side effect of Grastofil use is pain in your muscles or bones (musculoskeletal pain), which 

can be helped by taking standard pain relief medicines (analgesics). In patients undergoing a stem cell 

or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of the 

donor cells against the patient receiving the transplant; signs and symptoms include rash on the palms 

of your hands or soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your eyes, 

lungs, vagina and joints.  

 

In normal stem cell donors an increase in white blood cells (leukocytosis) and a decrease of platelets 

may be seen this reduces the ability of your blood to clot (thrombocytopenia), these will be monitored 

by your doctor. 

 

Very common side effects (may affect more than 1 in 10 people): 

 decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 

 low red blood cell count (anaemia) 

 headache 

 diarrhoea 

 vomiting 

 nausea 

 unusual hair loss or thinning (alopecia) 

 tiredness (fatigue) 

 soreness and swelling of the digestive tract lining which runs from the mouth to the anus 
(mucosal inflammation) 

 fever (pyrexia) 
 

Common side effects (may affect up to 1 in 10 people):  

 inflammation of the lung (bronchitis) 

 upper respiratory tract infection 

 urinary tract infection 

 decreased appetite 

 trouble sleeping (insomnia) 

 dizziness 

 decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 

 tingling or numbness of the hands or feet (paraesthesia) 

 low blood pressure (hypotension) 

 high blood pressure (hypertension) 

 cough 

 coughing up blood (haemoptysis)  

 pain in your mouth and throat (oropharyngeal pain) 

 nose bleeds (epistaxis) 

 constipation 

 oral pain 

 enlargement of the liver (hepatomegaly) 

 rash 

 redness of the skin (erythema) 

 muscle spasm 

 pain when passing urine (dysuria) 

 chest pain 

 pain 



 

69 

 generalised weakness (asthenia) 

 generally feeling unwell (malaise) 

 swelling in the hands and feet (oedema peripheral) 

 increase of certain enzymes in the blood 

 changes in blood chemistry 

 transfusion reaction 

 

Uncommon side effects (may affect up to 1 in 100 people):  

 increase in white blood cells (leukocytosis) 

 allergic reaction (hypersensitivity) 

 rejection of transplanted bone marrow (graft versus host disease) 

 high uric acid levels in the blood, which may cause gout (hyperuricaemia) (Blood uric acid 
increased) 

 liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 

 lungs do not function as they should, causing breathlessness (respiratory failure) 

 swelling and/or fluid in the lungs (pulmonary oedema) 

 inflammation of the lungs (interstitial lung disease) 

 abnormal x-rays of the lungs (lung infiltration) 

 bleeding from the lung (pulmonary haemorrhage) 

 lack of absorption of oxygen in the lung (hypoxia) 

 bumpy skin rash (rash macuo-papular) 

 disease which causes bones to become less dense, making them weaker, more brittle and likely 
to break (osteoporosis) 

 injection site reaction 
 

Rare side effects (may affect up to 1 in 1,000 people): 

 severe pain in the bones, chest, gut or joints (sickle anaemia with cell crisis) 

 sudden life-threatening allergic reaction (anaphylactic reaction) 

 pain and swelling of the joints, similar to gout (pseudogout) 

 a change in how your body regulates fluids within your body and may result in puffiness 
(fluidvolume disturbances) 

 inflammation of the blood vessels in the skin (cutaneous vasculitis) 

 plum-coloured, raised, painful sores on the limbs and sometimes the face and neck with a fever 
(Sweets syndrome) 

 worsening of rheumatoid arthritis 

 unusual change in the urine 

 bone density decreased 

 Inflammation of the aorta (the large blood vessel which transports blood from the heart to the 
body), see section 2. 

 

Reporting of side effects  

 

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V By reporting side effects you can help provide more information on the safety of this 

medicine.  

 

 

5. How to store Grastofil 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the outer carton and on the pre-filled 

syringe after EXP. The expiry date refers to the last day of the month. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

70 

Store in a refrigerator (2°C - 8°C). Do not freeze. 

 

Keep the pre-filled syringe in the carton in order to protect from light. 

 

Grastofil can be removed from the refrigerator and left at room temperature (not above 25℃) for a 
single period of up to 15 days that ends within the labelled expiry date. Once Grastofil has been out at 

room temperature it should not be put back into the refrigerator. Any Grastofil syringes that have been 

out of the refrigerator for longer than 15 days should not be used and should be disposed of in 

accordance with local requirements. 

Do not use Grastofil if you notice it is cloudy, or there is discoloration or there are particles in it. 

 

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 

dispose of medicines no longer required. These measures will help to protect the environment. 

 

6. Contents of the pack and other information 

 

What Grastofil contains  

 

 The active substance is filgrastim. Each mL of solution contains 60 million units (MU) 
(equivalent to 600 micrograms [μg]) of filgrastim. Each pre-filled syringe contains 48 MU (480 

μg) filgrastim in 0.5 mL solution.   

 The other ingredients are glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80 
and water for injections. See section 2 “What you need to know before you use Grastofil”.    

 

What Grastofil looks like and contents of the pack 

 

Grastofil is a clear colourless solution for injection or infusion. It is supplied in a pre-filled syringe 

marked with 1/40 printed markings from 0.1 mL to 1 mL on the syringe barrel, with an injection 

needle. Each pre-filled syringe contains 0.5 mL of solution. 

 

Grastofil is available in packs containing 1 and 5 pre-filled syringes.  

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Accord Healthcare S.L.U.  

World Trade Center  

Moll de Barcelona 

s/n, Edifici Est 6ª planta 

08039 Barcelona 

Spain                                                                                                                                 

 

Manufacturer 
 

Apotex Nederland B.V. 

Archimedesweg 2 

2333 CN Leiden  

Netherlands 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Eurogenerics SA/NV                                   

Telephone +32/2.479.78.78 

Lietuva                                                               

STADA Arzneimittel AG                                             

Telephone +49/6101.603.0 

  



 

71 

България 

STADA Arzneimittel AG                                

Telephone +49/6101.603.0 

Luxembourg/Luxemburg 
Eurogenerics SA/NV 

Telephone +32/2.479.78.78 

 

Česká republika 
STADA Pharma CZ s.r.o.                                

Telephone +420/257-888.111 

 

Magyarország                                         

STADA Arzneimittel AG                                 

Telephone +49/6101.603.0  

 

Danmark 
STADA Nordic ApS                                      

Telephone +45/44.85.99.99 

 

Malta 
PharmaMt Ltd. 

Telephone +356/21337008 

 

 

 

Deutschland 
STADAPHARM GmbH 

Telephone +49/6101.603.0 

 

 

 

Nederland 
Centrafarm BV                                                

Telephone +31/7650.81.000 

 

Eesti 

STADA Arzneimittel AG                              

Telephone +49/6101.603.0 

 

Norge 
STADA Arzneimittel AG                                            

Telephone +49/6101.603.0 

  

Ελλάδα 
Rafarm AEBE 

Κορίνθου 12, Ν. Ψυχικό, 15451, Αθήνα 

Telephone +30/2106776550  

 

 

Österreich 
STADA Arzneimittel Gesellschaft m.b.H.                                    

Telephone +43/1-367.85.85.0 

España 
Laboratorio STADA S.L. 

Telephone +34/93-473.88.89 

Polska 
STADA Poland Sp. z.oo.                                                        

Telephone +48/22 -737.79.20  

 

France 

EG LABO-Laboratoires Eurogenerics SAS  

Telephone +33/1-46.94.86.86 

 

Portugal                                                                        
Apotex Europe B.V.                                           

Telephone +(31) 71. 565.77.77  

 

Hrvatska 

STADA d.o.o                                                         

Telephone +385/1.3764.111 

 

România 

STADA Arzneimittel AG                                

Telephone +49/6101.603.0 

 

Ireland 
CLONMEL Healthcare Ltd. 

Telephone +353/52.61.77.777 

 

Slovenija                                                                       
STADA d.o.o.                                                      

Telephone +386/1-589.67.10 

 

Ísland 

STADA Arzneimittel AG  

Telephone +49/6101.603.0 

 

Slovenská republika 
STADA PHARMA Slovakia s.r.o. 

Telephone +421/2-5262.1933 

 

Italia 
CRINOS S.p.A.  

Telephone +39/02-89.421721 

 

Suomi/Finland                                                             

STADA Nordic ApS, Suomen sivuliike                                       

Telephone +358/207.416.888 

 

Κύπρος 

STADA Arzneimittel AG                                          

Telephone +49/6101.603.0 

 

Sverige                                                     

STADA Nordic ApS                                                   

Telephone +45/44.85.99.99 

 

Latvija                                                             

STADA Arzneimittel AG                                             

 

United Kingdom 

Thornton & Ross Ltd. 



 

72 

Telephone +49/6101.603.0 Telephone +44/1484-842.217  

 

This leaflet was last revised in MM/YYYY 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu  

 

--------------------------------------------------------------------------------------------------------------- 

 

The following information is intended for medical or healthcare professionals only:  
 

In order to improve the traceability of biological medicinal products, the name and the batch number 

of the administered product should be clearly recorded.  

 

If required, Grastofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 

(2 µg) 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 MU (15 µg) per mL, human 

serum albumin (HSA) should be added to a final concentration of 2 mg/mL. Example: In a final 

injection volume of 20 mL, total doses of filgrastim less than 30 MU (300 µg) should be given with 

0.2 mL of 200 mg/mL (20%) human albumin solution added. 

 

When diluted in 5% glucose, Grastofil is compatible with glass and a variety of plastics including 

PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET