Filgrastim Hexal

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
Each ml of solution contains 60 million units (MU) (equivalent to 600 micrograms [μg]) filgrastim*. 
Each pre-filled syringe contains 30 MU (equivalent to 300 μg) filgrastim in 0.5 ml. 
 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
Each ml of solution contains 96 million units (MU) (equivalent to 960 micrograms [μg]) filgrastim*. 
Each pre-filled syringe contains 48 MU (equivalent to 480 μg) filgrastim in 0.5 ml. 
 
* recombinant methionylated human granulocyte-colony stimulating factor (G-CSF) produced in 
E. coli by recombinant DNA technology. 
 
Excipient with known effect 
Each ml of solution contains 50 mg sorbitol (E420). 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection or infusion in pre-filled syringe (injection or infusion). 
Clear, colourless to slightly yellowish solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
- Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients 

treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic 
myeloid leukaemia and myelodysplastic syndromes) and reduction in the duration of 
neutropenia in patients undergoing myeloablative therapy followed by bone marrow 
transplantation considered to be at increased risk of prolonged severe neutropenia. 

 
The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic 
chemotherapy. 

 
- 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 109/l, and a history of severe or recurrent infections, 
long term administration of filgrastim is indicated to increase neutrophil counts and to reduce 
the incidence and duration of infection-related events. 

 
- Treatment of persistent neutropenia (ANC ≤ 1.0 x 109/l) in patients with advanced HIV 

infection, in order to reduce the risk of bacterial infections when other options to manage 
neutropenia are inappropriate. 

 



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4.2 Posology and method of administration 
 
Filgrastim therapy should only be given in collaboration with an oncology centre which has 
experience in G-CSF treatment and haematology and has the necessary diagnostic facilities. The 
mobilisation and apheresis procedures should be performed in collaboration with an oncology-
haematology centre with acceptable experience in this field and where the monitoring of 
haematopoietic progenitor cells can be correctly performed. 
 
Established cytotoxic chemotherapy 
 
Posology 
 
The recommended dose of filgrastim is 0.5 MU/kg/day (5 μg/kg/day). The first dose of filgrastim 
should be administered at least 24 hours after cytotoxic chemotherapy. In randomised clinical trials, a 
subcutaneous dose of 230 μg/m2/day (4.0 to 8.4 μg/kg/day) was used. 
 
Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the 
neutrophil count has recovered to the normal range. Following established chemotherapy for solid 
tumours, lymphomas, and lymphoid leukaemia, it is expected that the duration of treatment required to 
fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute 
myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on 
the type, dose and schedule of cytotoxic chemotherapy used. 
 
In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 
1 - 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, 
filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil 
count has recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to the 
time of the expected neutrophil nadir, is not recommended. 
 
Method of administration 
 
Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 
5% glucose solution given over 30 minutes (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 filgrastim is 1.0 MU/kg/day (10 μg/kg/day). The first dose of 
filgrastim should be administered at least 24 hours following cytotoxic chemotherapy and at least 
24 hours after bone marrow infusion. 
 
Once the neutrophil nadir has been passed, the daily dose of filgrastim should be titrated against the 
neutrophil response as follows: 
 
Neutrophil count Filgrastim dose adjustment 
> 1.0 x 109/l for 3 consecutive days Reduce to 0.5 MU/kg/day (5 μg/kg/day) 
Then, if ANC remains > 1.0 x 109/l for 
3 more consecutive days Discontinue filgrastim  

If the ANC decreases to < 1.0 x 109/l during the treatment period, the dose of filgrastim 
should be re-escalated according to the above steps 
ANC = absolute neutrophil count 
 



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Method of administration 
 
Filgrastim may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 
24 hour subcutaneous infusion. Filgrastim should be diluted in 20 ml of 5% glucose solution (see 
section 6.6). 
 
For the mobilisation of PBPCs in patients undergoing myelosuppressive or myeloablative therapy 
followed by autologous PBPC transplantation 
 
Posology 
 
The recommended dose of filgrastim for PBPC mobilisation when used alone is 
1.0 MU/kg/day (10 μg/kg/day) for 5 - 7 consecutive days. Timing of leukapheresis: 
1 or 2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional 
leukaphereses may be necessary. Filgrastim dosing should be maintained until the last leukapheresis. 
 
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 
0.5 MU/kg/day (5 μg/kg/day) from the first day after completion of chemotherapy until the expected 
neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis 
should be performed during the period when the ANC rises from < 0.5 x 109/l to > 5.0 x 109/l. For 
patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other 
circumstances, additional leukaphereses are recommended. 
 
Method of administration 
 
Filgrastim for PBPC mobilisation when used alone: 
Filgrastim may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For 
infusions filgrastim should be diluted in 20 ml of 5% glucose solution (see section 6.6). 
 
Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy: 
Filgrastim 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, filgrastim should be administered at 
1.0 MU/kg/day (10 μg/kg/day) for 4 - 5 consecutive days. Leukapheresis should be started at day 5 
and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipient bodyweight. 
 
Method of administration 
 
Filgrastim should be given by subcutaneous injection. 
 
In patients with severe chronic neutropenia (SCN) 
 
Posology 
 
Congenital neutropenia 
The recommended starting dose is 1.2 MU/kg/day (12 μg/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 μg/kg/day) as a single dose or in divided doses. 
 
Dose adjustment 
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has 
reached and can be maintained at more than 1.5 x 109/l. When the response has been obtained, the 



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minimal effective dose to maintain this level should be established. Long-term daily administration is 
required to maintain an adequate neutrophil count. After 1 - 2 weeks of therapy, the initial dose may 
be doubled or halved depending upon the patient's response. Subsequently the dose may be 
individually adjusted every 1 - 2 weeks to maintain the average neutrophil count between 1.5 x 109/l 
and 10 x 109/l. A faster schedule of dose escalation may be considered in patients presenting with 
severe infections. In clinical trials, 97% of patients who responded had a complete response at doses 
≤ 24 μg/kg/day. The long-term safety of filgrastim administration above 24 μg/kg/day in patients with 
SCN has not been established. 
 
Method of administration 
 
Congenital, idiopathic or cyclic neutropenia: Filgrastim should be given by subcutaneous injection. 
 
In patients with HIV infection 
 
Posology 
 
For reversal of neutropenia 
The recommended starting dose of filgrastim is 0.1 MU/kg/day (1 μg/kg/day), with titration up to a 
maximum of 0.4 MU/kg/day (4 μg/kg/day) until a normal neutrophil count is reached and can be 
maintained (ANC > 2.0 x 109/l). In clinical studies, > 90% of patients responded at these doses, 
achieving reversal of neutropenia in a median of 2 days. 
 
In a small number of patients (< 10%), doses up to 1.0 MU/kg/day (10 μg/kg/day) were required to 
achieve reversal of neutropenia. 
 
For maintaining normal neutrophil counts 
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal 
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 
30 MU/day (300 μg/day) is recommended. Further dose adjustment may be necessary, as determined 
by the patient's ANC, to maintain the neutrophil count at > 2.0 x 109/l. In clinical studies, dosing with 
30 MU/day (300 μg/day) on 1 - 7 days per week was required to maintain the ANC > 2.0 x 109/l, with 
the median dose frequency being 3 days per week. Long-term administration may be required to 
maintain the ANC > 2.0 x 109/l. 
 
Method of administration 
 
Reversal of neutropenia or maintaining normal neutrophil counts: Filgrastim should be given by 
subcutaneous injection. 
 
Elderly 
 
Clinical trials with filgrastim have included a small number of elderly patients but special studies have 
not been performed in this group and therefore specific dosage recommendations cannot be made. 
 
Renal impairment 
 
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it 
exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. 
Dose adjustment is not required in these circumstances. 
 
Paediatric use in the SCN and cancer settings 
 
Sixty-five percent of the patients studied in the SCN trial program were under 18 years of age. The 
efficacy of treatment was clear for this age-group, which included most patients with congenital 
neutropenia. There were no differences in the safety profiles for paediatric patients treated for SCN. 
 



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Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 
similar in both adults and children receiving cytotoxic chemotherapy. 
The dosage recommendations in paediatric patients are the same as those in adults receiving 
myelosuppressive cytotoxic chemotherapy. 
 
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 
 
Special warnings and precautions across indications 
 
Hypersensitivity 
 
Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment has 
been reported in patients treated with filgrastim. Permanently discontinue Filgrastim HEXAL in 
patients with clinically significant hypersensitivity. Do not administer Filgrastim HEXAL to patients 
with a history of hypersensitivity to filgrastim or pegfilgrastim. 
 
Pulmonary adverse effects 
 
Pulmonary adverse effects, in particular interstitial lung disease, have been reported after G-CSF 
administration. Patients with a recent history of lung infiltrates or pneumonia may be at higher risk. 
The onset of pulmonary signs, such as cough, fever and dyspnoea in association with radiological 
signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of 
acute respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate 
treatment given in these cases. 
 
Glomerulonephritis 
 
Glomerulonephritis has been reported in patients receiving filgrastim or pegfilgrastim. Generally, 
events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim or 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 pain 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 
 
G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some non-
myeloid cells in vitro. 



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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 acute myelogenous leukaemia 
(AML), filgrastim should be administered with caution. The safety and efficacy of filgrastim 
administration in de novo AML patients aged < 55 years with good cytogenetics [t(8;21), t(15;17), and 
inv(16)] have not been established. 
 
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 109/l). 
 
Leukocytosis 
 
White blood cell counts of 100 x 109/l or greater have been observed in less than 5% of cancer patients 
receiving filgrastim at doses above 0.3 MU/kg/day (3 μg/kg/day). No undesirable effects directly 
attributable to this degree of leukocytosis have been reported. However, in view of the potential risks 
associated with severe leukocytosis, a white blood cell count should be performed at regular intervals 
during filgrastim therapy. If leukocyte counts exceed 50 x 109/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 109/l. 
 
Immunogenicity 
 
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of 
antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all 
biologics; however, they have not been associated with neutralising activity at present. 
 
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. 
 



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Risks associated with increased doses of chemotherapy 
 
Special caution should be used when treating patients with high-dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may 
lead to increased toxicities including cardiac, pulmonary, neurologic, and dermatologic effects (please 
refer to the prescribing information of the specific chemotherapy agents used). 
 
Effect of chemotherapy on erythrocytes and thrombocytes 
 
Treatment with 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 agents 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. 
 
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 inflammatory markers 
(e.g. C-reactive protein and white blood cell count) were raised. In most cases aortitis was diagnosed 
by CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8. 
 
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 optimum method. The choice of mobilisation method should be considered in 
relation to the overall objectives of treatment for an individual patient. 
 



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Prior exposure to cytotoxic agents 
 
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient 
mobilisation of PBPC to achieve the recommended minimum yield (≥ 2.0 x 106 CD34+ cells/kg) or 
acceleration of platelet recovery to the same degree. 
 
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may 
adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and 
carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation 
may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU 
together with filgrastim has been shown to be effective for progenitor mobilisation. When a PBPC 
transplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in the 
treatment course of the patient. Particular attention should be paid to the number of progenitors 
mobilised in such patients before the administration of high-dose chemotherapy. If yields are 
inadequate, as measured by the criteria above, alternative forms of treatment not requiring progenitor 
support should be considered. 
 
Assessment of progenitor cell yields 
 
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular 
attention should be paid to the method of quantitation. The results of flow cytometric analysis of 
CD34+ cell numbers vary depending on the precise methodology used and, recommendations of 
numbers based on studies in other laboratories need to be interpreted with caution. 
 
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of 
platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. 
 
The recommendation of a minimum yield of ≥ 2.0 x 106 CD34+ cells/kg is based on published 
experience resulting in adequate haematologic reconstitution. Yields in excess of this appear to 
correlate with more rapid recovery, those below with slower recovery. 
 
Special precautions in normal donors undergoing PBPC mobilisation 
 
Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be 
considered for the purposes of allogeneic stem cell transplantation. 
 
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory 
eligibility criteria for stem cell donation with special attention to haematological values and infectious 
disease. 
 
The safety and efficacy of filgrastim have not been assessed in normal donors < 16 years or > 60 years. 
 
Transient thrombocytopenia (platelets < 100 x 109/l) following filgrastim administration and 
leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets 
< 50 x 109/l were reported and attributed to the leukapheresis procedure. 
 
If more than one leukapheresis is required, particular attention should be paid to donors with 
platelets < 100 x 109/l prior to leukapheresis; in general apheresis should not be performed if 
platelets < 75 x 109/l. 
 
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 
in haemostasis. 
 
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices 
return to normal. 
 



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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 PBPCs mobilised with filgrastim 
 
Current data indicate that immunological interactions between the allogeneic PBPC graft and the 
recipient may be associated with an increased risk of acute and chronic GvHD when compared with 
bone marrow transplantation. 
 
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 
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 these events. 
 
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 
established. 
 
Special precautions in patients with HIV infection 
 
Blood cell counts 
 
Absolute neutrophil count (ANC) should be monitored closely, especially during the first few weeks 
of filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in 
neutrophil count to the initial dose of filgrastim. It is recommended that the ANC is measured daily for 
the first 2 - 3 days of filgrastim administration. Thereafter, it is recommended that the ANC is 
measured at least twice per week for the first 2 weeks and subsequently once per week or once every 



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other week during maintenance therapy. During intermittent dosing with 30 MU/day (300 μg/day) of 
filgrastim, there can be wide fluctuations in the patient's ANC over time. In order to determine a 
patient's trough or nadir ANC, it is recommended that blood samples are taken for ANC measurement 
immediately prior to any scheduled dosing with filgrastim. 
 
Risk associated with increased doses of myelosuppressive medicinal products 
 
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to 
myelosuppressive treatments. As a result of the potential to receive higher doses or a greater number 
of these 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. 
 
Excipients 
 
Filgrastim HEXAL contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) must 
not be given this medicine unless strictly necessary. 
 
Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose 
intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-
threatening and should be contraindicated in this population unless there is an overwhelming clinical 
need and no alternatives are available. 
 
A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given 
this medicinal product. 
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade 
name of the administered product should be clearly recorded in the patient file. 
 
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 trials. 
 
Since lithium promotes the release of neutrophils, lithium is likely to potentiate the effect of filgrastim. 
Although this interaction has not been formally investigated, there is no evidence that such an 
interaction is harmful. 
 
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 



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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 HEXAL 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 HEXAL 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). 
 
4.7 Effects on ability to drive and use machines 
 
Filgrastim may have a 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 
 
a. 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. 
 
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 trials in cancer patients 
musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients. 
 
b. Tabulated summary of adverse reactions 
 
The data in the tables below describe adverse reactions reported from clinical trials 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)  

Very rare  
(< 1/10,000) 

Infections and 
infestations 
 

 Sepsis 
Bronchitis 
Upper respiratory 
tract infection 
Urinary tract 
infection 

   



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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)  

Very rare  
(< 1/10,000) 

Blood and 
lymphatic 
system 
disorders 

Thrombocyto-
penia 
Anaemiae 

Splenomegalya 
Haemoglobin 
decreasede 

Leukocytosisa  Splenic 
rupturea 
Sickle cell 
anaemia with 
crisis 

 

Immune sys-
tem disorders 

  Hypersensitivity 
Drug 
hypersensitivitya 
Graft versus host 
diseaseb 

Anaphylactic 
reaction 

 

Metabolism 
and nutrition 
disorders 

 Decreased 
Appetitee 
Blood lactate 
dehydrogenase 
increased 

Hyperuricaemia 
Blood uric acid 
increased 

Blood glucose 
decreased 
Pseudogouta 
(Chondrocal-
cinosis Pyro-
phosphate) 
Fluid volume 
disturbances 

 

Psychiatric 
disorders 

 Insomnia    

Nervous 
system 
disorders 

Headachea Dizziness 
Hypoaesthesia 
Paraesthesia 

   

Vascular 
Disorders 

 Hypertension 
Hypotension 

Veno-occlusive 
diseased 
 

Aortitis 
Capillary leak 
syndromea 
 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Haemoptysis 
Dyspnoea 
Cougha 
Oropharyngeal 
paina, e 
Epistaxis 

Acute 
respiratory 
distress 
syndromea 
Respiratory 
failurea 
Pulmonary 
oedemaa 
Pulmonary 
haemorrhage 
Interstitial lung 
diseasea 
Lung 
infiltrationa 
Hypoxia 

  

Gastrointesti-
nal disorders 

Diarrhoeaa, e 
Vomitinga, e 
Nauseaa 

Oral pain 
Constipatione 

   



14 

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)  

Very rare  
(< 1/10,000) 

Hepatobiliary 
disorders 

 Hepatomegaly 
Blood alkaline 
phosphatase 
increased 

Aspartate ami-
notransferase 
increased 
Gamma-
glutamyl 
transferase 
increased 

  

Skin and 
subcutaneous 
tissue 
disorders 

Alopeciaa Rasha 
Erythema 

Maculopapular 
rash 

Cutaneous 
vasculitisa 
Sweets 
syndrome 
(acute febrile 
neutrophilic 
dermatosis) 

 

Musculoskele-
tal and 
connective 
tissue 
disorders 

Musculoskele-
tal painc 

Muscle spasms Osteoporosis Bone density 
decreased 
Exacerbation of 
rheumatoid 
arthritis 

 

Renal and 
urinary 
disorders 

 Dysuria 
Haematuria 

Proteinuria Glomerulo-
nephritis 
Urine 
abnormality 

 

General 
disorders and 
administra-
tion site 
conditions 

Fatiguea 
Mucosal 
inflammationa 
Pyrexia 

Chest paina 
Paina  
Astheniaa 
Malaisee 
Oedema 
peripherale 

Injection site 
reaction 

  

Injury, 
poisoning and 
procedural 
complications 

 Transfusion 
reactione 

   

a See section c (Description of selected adverse reactions) 
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow 
transplantation (see section c) 
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 mobilisation 
e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with 
the sequelae of the underlying malignancy or cytotoxic chemotherapy 
 
c. 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 



15 

post marketing experience. Overall, reports were more common after IV administration. In some cases, 
symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be 
permanently discontinued in patients who experience a serious allergic reaction. 
 
Pulmonary adverse events 
 
In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung 
disease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome of 
respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see 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, taking multiple 
chemotherapy medications 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 109/l) was observed in 41% of normal donors and transient 
thrombocytopenia (platelets < 100 x 109/l) following filgrastim 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 patients with cancer treated with 
filgrastim.  
 
GvHD 
 
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see section 4.4 and 5.1). 
 
d. Paediatric population 
 
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 
similar in both adults and children receiving cytotoxic chemotherapy, suggesting no age-related 
differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was 
musculoskeletal pain‚ which is no different from the experience in the adult population. 
 
There is insufficient data to further evaluate filgrastim use in paediatric subjects. 
 



16 

e. Other special populations 
 
Geriatric use 
 
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 geriatric subjects for other approved filgrastim 
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 filgrastim overdosage 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 
 
Filgrastim HEXAL is a biosimilar medicinal product. Detailed information is available on the website 
of the European Medicines Agency http://www.ema.europa.eu. 
 
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils 
from the bone marrow. Filgrastim HEXAL 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 - 2 days, and to normal 
levels within 1 - 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. 
 



17 

Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into 
the 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 PBPC accelerates 
haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need 
for platelet transfusions. 
 
Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid 
haematological recovery, leading to a significant decrease in time to unsupported platelet recovery 
when compared with allogeneic bone marrow transplantation. 
 
One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow 
transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment 
related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective 
international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of 
GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the 
results of nine prospective randomized trials, eight retrospective studies and one 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 transplantation 

Publication Period of Study N 
Acute Grade 
II - IV GvHD 

Chronic 
GvHD TRM 

Meta-Analysis 
(2003) 

  
1986 - 2001a 

  
1198 

1.08  
(0.87, 1.33) 

1.02  
(0.82, 1.26) 

0.70  
(0.38, 1.31) 

European 
Retrospective  
Study (2004) 

  
  
1992 - 2002b 

  
  
1789 

  
1.33  
(1.08, 1.64) 

  
1.29  
(1.02, 1.61) 

  
1.73  
(1.30, 2.32) 

International 
Retrospective  
Study (2006) 

  
  
1995 - 2000b 

  
  
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 1 MU/kg/day (10 μg/kg/day) dose administered subcutaneously for 
4 - 5 consecutive days allows a collection of ≥ 4 x 106 CD34+ cells/kg recipient body weight in the 
majority of the donors after 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 medication. There is no evidence that patients with 
HIV infection treated with filgrastim show an increase in HIV replication. 
 
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on 
human endothelial cells. 
 
5.2 Pharmacokinetic properties 
 
Randomised, double-blind, single and multiple dose, crossover studies in 204 healthy volunteers 
showed that the pharmacokinetic profile of Filgrastim HEXAL was comparable to that of the reference 
product after subcutaneous and intravenous administration. 
 



18 

Absorption 
 
A single subcutaneous dose of 0.5 MU/kg (5 µg/kg) resulted in maximum serum concentrations after a 
tmax of 4.5 ± 0.9 hours (mean ± SD). 
 
Distribution 
 
The volume of distribution in blood is approximately 150 ml/kg. Following subcutaneous 
administration of recommended doses, serum concentrations were maintained above 10 ng/ml for 
8 - 16 hours. There is a positive linear correlation between the dose and the serum concentration of 
filgrastim, whether administered intravenously or subcutaneously. 
 
Elimination 
 
The median serum elimination half-life (t1/2) of filgrastim after single subcutaneous doses ranged from 
2.7 hours (1.0 MU/kg, 10 µg/kg) to 5.7 hours (0.25 MU/kg, 2.5 µg/kg) and was prolonged after 7 days 
of dosing to 8.5 - 14 hours, respectively. 
Continuous infusion with filgrastim over a period of up to 28 days, in patients recovering from 
autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and 
comparable elimination half-lives. 
 
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 foetal weight were observed. 
 
Based on reported data for another filgrastim product similar to the reference filgrastim product, 
comparable findings plus increased foetal 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 observed adverse 
effect level for embryo-foetal 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 foetal 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. 
 
 



19 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Glutamic acid 
Sorbitol (E420) 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Filgrastim HEXAL must not be diluted with sodium chloride solution. 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
Diluted filgrastim may be adsorbed to glass and plastic materials, unless it is diluted in 
glucose 50 mg/ml (5%) solution (see section 6.6). 
 
6.3 Shelf life 
 
36 months. 
 
After dilution: 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). 
 
Keep the pre-filled syringe in the outer carton in order to protect from light. 
 
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from 
the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 
72 hours. At the end of this period, the product should not be put back in the refrigerator and should be 
disposed of. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Pre-filled syringe (type I glass) with injection needle (stainless steel), with or without a needle safety 
guard, containing 0.5 ml solution. 
 
Pack sizes of 1, 3, 5 or 10 pre-filled syringes. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of filgrastim. 
 



20 

Filgrastim HEXAL contains no preservative. In view of the possible risk of microbial contamination, 
Filgrastim HEXAL syringes are for single use only. 
 
Dilution prior to administration (optional) 
 
If required, Filgrastim HEXAL may be diluted in glucose 50 mg/ml (5%) solution. 
 
Dilution to a final concentration < 0.2 MU/ml (2 μg/ml) is not recommended at any time. 
 
For patients treated with filgrastim diluted to concentrations < 1.5 MU/ml (15 μg/ml), human serum 
albumin (HSA) should be added to a final concentration of 2 mg/ml. 
 
Example: In a final volume of 20 ml, total doses of filgrastim less than 30 MU (300 μg) should be 
given with 0.2 ml of human serum albumin 200 mg/ml (20%) solution Ph. Eur. added. 
 
When diluted in glucose 50 mg/ml (5%) solution, filgrastim is compatible with glass and a variety of 
plastics including polyvinylchloride, polyolefin (a copolymer of polypropylene and polyethylene) and 
polypropylene. 
 
Using the pre-filled syringe with a needle safety guard 
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 
plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger. 
 
Using the pre-filled syringe without a needle safety guard 
 
Administer the dose as per standard protocol. 
 
Disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
EU/1/08/496/001 
EU/1/08/496/002 
EU/1/08/496/003 
EU/1/08/496/004 
EU/1/08/496/009 
EU/1/08/496/010 
EU/1/08/496/011 
EU/1/08/496/012 
 



21 

Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
EU/1/08/496/005 
EU/1/08/496/006 
EU/1/08/496/007 
EU/1/08/496/008 
EU/1/08/496/013 
EU/1/08/496/014 
EU/1/08/496/015 
EU/1/08/496/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 06 February 2009 
Date of latest renewal: 13 November 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
<{MM/YYYY}> 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 



23 

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) 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Sandoz GmbH  
Biochemiestr. 10 
6336 Langkampfen 
Austria 
 
 
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 and any agreed 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. 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
Filgrastim  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 30 million units (equivalent to 300 micrograms) filgrastim in 0.5 ml 
(60 MU/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: glutamic acid, polysorbate 80, water for injections and sorbitol (E420). See package leaflet 
for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion in pre-filled syringe. 
 
1 pre-filled syringe without needle safety guard 
3 pre-filled syringes without needle safety guard 
5 pre-filled syringes without needle safety guard 
10 pre-filled syringes without needle safety guard 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use only. Read the package leaflet before use. 
Subcutaneous or intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE 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 
After dilution use within 24 hours. 
 
 



27 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). 
Keep the pre-filled 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 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/496/009 
EU/1/08/496/010 
EU/1/08/496/011 
EU/1/08/496/012 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Filgrastim HEXAL 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: 



28 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 48 million units (equivalent to 480 micrograms) filgrastim in 0.5 ml 
(96 MU/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: glutamic acid, polysorbate 80, water for injections and sorbitol (E420). See package leaflet 
for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion in pre-filled syringe. 
 
1 pre-filled syringe without needle safety guard 
3 pre-filled syringes without needle safety guard 
5 pre-filled syringes without needle safety guard 
10 pre-filled syringes without needle safety guard 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use only. Read the package leaflet before use. 
Subcutaneous or intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE 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 
After dilution use within 24 hours. 
 
 



29 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). 
Keep the pre-filled 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 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/496/013 
EU/1/08/496/014 
EU/1/08/496/015 
EU/1/08/496/016 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Filgrastim HEXAL 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: 



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – PRE-FILLED SYRINGE WITH A NEEDLE SAFETY GUARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 30 million units (equivalent to 300 micrograms) filgrastim in 0.5 ml 
(60 MU/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: glutamic acid, polysorbate 80, water for injections and sorbitol (E420). See package leaflet 
for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion in pre-filled syringe. 
 
1 pre-filled syringe with a needle safety guard 
3 pre-filled syringes with a needle safety guard 
5 pre-filled syringes with a needle safety guard 
10 pre-filled syringes with a needle safety guard 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use only. Read the package leaflet before use. 
Subcutaneous or intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE 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 
After dilution use within 24 hours. 
 
 



31 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). 
Keep the pre-filled 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 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/496/001 
EU/1/08/496/002 
EU/1/08/496/003 
EU/1/08/496/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Filgrastim HEXAL 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: 



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – PRE-FILLED SYRINGE WITH A NEEDLE SAFETY GUARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 48 million units (equivalent to 480 micrograms) filgrastim in 0.5 ml 
(96 MU/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: glutamic acid, polysorbate 80, water for injections and sorbitol (E420). See package leaflet 
for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion in pre-filled syringe. 
 
1 pre-filled syringe with a needle safety guard 
3 pre-filled syringes with a needle safety guard 
5 pre-filled syringes with a needle safety guard 
10 pre-filled syringes with a needle safety guard 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use only. Read the package leaflet before use. 
Subcutaneous or intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE 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 
After dilution use within 24 hours. 
 
 



33 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). 
Keep the pre-filled 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 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/496/005 
EU/1/08/496/006 
EU/1/08/496/007 
EU/1/08/496/008 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Filgrastim HEXAL 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: 



34 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE / PRE-FILLED SYRINGE WITH A NEEDLES SAFETY GUARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Filgrastim HEXAL 30 MU/0.5 ml injection or infusion 
 
Filgrastim 
SC/IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 



35 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE / PRE-FILLED SYRINGE WITH A NEEDLE SAFETY GUARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Filgrastim HEXAL 48 MU/0.5 ml injection or infusion 
 
Filgrastim 
SC/IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



37 

Package leaflet: Information for the user 
 

Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or 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. 
 
What is in this leaflet 
 
1. What Filgrastim HEXAL is and what it is used for 
2. What you need to know before you use Filgrastim HEXAL 
3. How to use Filgrastim HEXAL 
4. Possible side effects 
5. How to store Filgrastim HEXAL 
6. Contents of the pack and other information 
 
 
1. What Filgrastim HEXAL is and what it is used for 
 
Filgrastim HEXAL is a white blood cell growth factor (granulocyte colony stimulating factor) and 
belongs to a group of proteins 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. Filgrastim HEXAL 
works by encouraging 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 HEXAL stimulates the bone marrow to produce new 
white cells quickly. 
 
Filgrastim HEXAL 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; 
• 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; 

• 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. 
 
 
2. What you need to know before you use Filgrastim HEXAL 
 
Do not use Filgrastim HEXAL 
- if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in 

section 6). 
 



38 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Filgrastim HEXAL. 
 
Please tell your doctor before starting treatment if you have: 
- osteoporosis (bone disease); 
- sickle cell anaemia, as Filgrastim HEXAL may cause sickle cell crisis. 
 
Please tell your doctor immediately during treatment with Filgrastim HEXAL, if you: 
- 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]. 

- 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). 

 
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 
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 Filgrastim HEXAL unless instructed by your doctor. 
 
If you are a stem cell donor, you must be aged between 16 and 60 years. 
 
Take special care with other products that stimulate white blood cells. 
Filgrastim HEXAL is one of a group of products that stimulate the production of white blood cells. 
Your healthcare professional should always record the exact product you are using. 
 
Other medicines and Filgrastim HEXAL 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy and breast-feeding 
Filgrastim HEXAL has not been tested in pregnant or breast-feeding women. 
Filgrastim HEXAL is not recommended during pregnancy. 
 
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 Filgrastim HEXAL treatment, please inform your doctor. 
 



39 

Unless your doctor directs you otherwise, you must stop breast feeding if you use Filgrastim HEXAL. 
 
Driving and using machines 
Filgrastim HEXAL 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 taking Filgrastim 
HEXAL and before driving or operating machinery. 
 
Filgrastim HEXAL contains sorbitol 
 
Filgrastim HEXAL contains sorbitol (E420). 
 
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. 
 
 
3. How to use Filgrastim HEXAL 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 
 
How is Filgrastim HEXAL given and how much should I take? 
 
Filgrastim HEXAL 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). The usual dose varies depending on your illness and weight. Your doctor will 
tell you how much Filgrastim HEXAL you should take. 
 
Patients having a bone marrow transplant after chemotherapy: 
You will normally receive your first dose of Filgrastim HEXAL at least 24 hours after your 
chemotherapy and at least 24 hours after receiving your bone marrow transplant. 
 
You, or people caring for you, can be taught how to give subcutaneous injections so that you can 
continue your treatment at home. However, you should not attempt this unless you have been properly 
trained first by your health care provider. 
 
How long will I have to take Filgrastim HEXAL? 
 
You will need to take Filgrastim HEXAL 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 Filgrastim HEXAL. 
 
Use in children 
 
Filgrastim HEXAL is used to treat children who are receiving chemotherapy or who suffer from 
severe low white blood cell count (neutropenia). The dosing in children receiving chemotherapy is the 
same as for adults. 
 
If you use more Filgrastim HEXAL than you should 
 
Do not increase the dose your doctor has given you. If you think you have injected more than you 
should, contact your doctor as soon as possible. 
 



40 

If you forget to use Filgrastim HEXAL 
 
If you have missed an injection, or injected too little, contact your doctor as soon as possible. Do not 
take a double dose to make up for any missed doses. 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Please 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).  

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

• if 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]. 

• if 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). 

• if you have any of the following or combination of the following side effects: 
- 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. 

• if you have a combination of any of the following symptoms: 
- 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. 

• if 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. 

 
A common side effect of filgrastim 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. Very commonly seen in normal stem cell donors is increase in white blood 
cells (leukocytosis) and decrease of platelets which reduces the ability of 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) 



41 

• 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 
 



42 

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, pharmacist 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 Filgrastim HEXAL 
 
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 carton and on the syringe label 
after EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C). 
Keep the pre-filled syringe in the outer carton in order to protect from light. 
Accidental freezing will not harm Filgrastim HEXAL. 
 
The syringe can be removed from the refrigerator and left at room temperature for a single period of 
maximum 72 hours (but not above 25°C). At the end of this period, the product should not be put back 
in the refrigerator and should be disposed of. 
 
Do not use this medicine if you notice discolouration, cloudiness or particles, it should be a clear, 
colourless to slightly yellowish liquid. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Filgrastim HEXAL contains 
 
- The active substance is filgrastim. 

Filgrastim HEXAL 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe: Each 
pre-filled syringe contains 30 MU filgrastim in 0.5 ml, corresponding to 60 MU/ml. 
Filgrastim HEXAL 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe: Each 
pre-filled syringe contains 48 MU filgrastim in 0.5 ml, corresponding to 96 MU/ml 

- The other ingredients are glutamic acid, sorbitol (E420), polysorbate 80 and water for injections. 
 



43 

What Filgrastim HEXAL looks like and contents of the pack 
 
Filgrastim HEXAL is a clear, colourless to slightly yellowish solution for injection or infusion in pre-
filled syringe. 
 
Filgrastim HEXAL is available in packs containing 1, 3, 5 or 10 pre-filled syringes with injection 
needle and with or without a needle safety guard. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
HEXAL AG 
Industriestr. 25 
83607 Holzkirchen 
Germany 
 
Manufacturer 
 
Sandoz GmbH 
Biochemiestr. 10 
6336 Langkampfen 
Austria 
 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------------ 
 
Instructions on how to inject yourself  
 
This section contains information on how to give yourself an injection of Filgrastim HEXAL. It is 
important that you do not try to give yourself the injection unless you have received special 
training from your doctor or nurse. Filgrastim HEXAL is provided with or without a needle safety 
guard and you will be shown how to use this by your doctor or nurse. If you are not sure about giving 
the injection or you have any questions, please ask your doctor or nurse for help. 
 
1. Wash your hands. 
2. Remove one syringe from the pack and remove the protective cap from the injection needle. 

Syringes are embossed with graduation rings in order to enable partial use if required. Each 
graduation ring corresponds to a volume of 0.1 ml. If partial use of a syringe is required, remove 
unwanted solution before injection. 

3. Clean the skin at the injection site using an alcohol wipe. 
4. Form a skin fold by pinching the skin between thumb and forefinger. 
5. Insert the needle into the skin fold with a quick, firm action. Inject the Filgrastim HEXAL 

solution as you have been shown by your doctor. You should check with your doctor or 
pharmacist if you are not sure. 

 
Pre-filled syringe without needle safety guard 
 
6. Always keeping your skin pinched, depress the plunger slowly and evenly. 
7. After injecting the liquid, remove the needle and let go of your skin. 
8. Put the used syringe in the disposal container. Use each syringe only for one 

injection. 
 



44 

Pre-filled syringe with needle safety guard 
 
6. Always keeping your skin pinched, depress the plunger slowly and evenly 

until the entire dose has been given and the plunger cannot be depressed any 
further. Do not release the pressure on the plunger! 

7. After injecting the liquid, remove the needle while maintaining pressure on 
the plunger and then let go of your skin. 

8. Let go of the plunger. The needle safety guard will rapidly move to cover the 
needle. 

9. Discard any unused product or waste material. Only use each syringe for one injection. 
 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used. Accidental exposure to freezing temperatures does not adversely affect the stability of Filgrastim 
HEXAL. 
 
Filgrastim HEXAL contains no preservative: In view of the possible risk of microbial contamination, 
Filgrastim HEXAL syringes are for single use only. 
 
Dilution prior to administration (optional) 
 
If required, Filgrastim HEXAL may be diluted in glucose 50 mg/ml (5%) solution. Filgrastim HEXAL 
must not be diluted with sodium chloride solutions. 
 
Dilution to a final concentration < 0.2 MU/ml (2 μg/ml) is not recommended at any time. 
 
For patients treated with filgrastim diluted to concentrations < 1.5 MU/ml (15 μg/ml), human serum 
albumin (HSA) should be added to a final concentration of 2 mg/ml. 
 
Example: In a final volume of 20 ml, total doses of filgrastim less than 30 MU (300 μg) should be 
given with 0.2 ml of human serum albumin 200 mg/ml (20%) solution Ph. Eur. added. 
 
When diluted in glucose 50 mg/ml (5%) solution, filgrastim is compatible with glass and a variety of 
plastics including polyvinylchloride, polyolefin (a copolymer of polypropylene and polyethylene) and 
polypropylene. 
 
After dilution: 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. 
 
Using the pre-filled syringe with a needle safety guard 
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 
plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger. 
 
Using the pre-filled syringe without a needle safety guard 
 
Administer the dose as per standard protocol. 
 



45 

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


	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