Biograstim

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 30 MIU/0.5 mL solution for injection or infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of solution for injection or infusion contains 60 million international units [MIU] (600 µg) 
of filgrastim. 
 
Each pre-filled syringe contains 30 MIU (300 µg) of filgrastim in 0.5 mL solution for injection or 
infusion. 
 
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced in 
Escherichia coli K802 by recombinant DNA technology. 
 
Excipient with known effect 
Each mL of solution contains 50 mg of sorbitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection or infusion 
 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Biograstim 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 filgrastim are similar in adults and children receiving cytotoxic chemotherapy. 
 
Biograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC). 
 
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 Biograstim is indicated to increase neutrophil counts and to reduce the 
incidence and duration of infection-related events. 
 
Biograstim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 
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. 
 
4.2 Posology and method of administration 
 

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Special requirements 
 
Filgrastim 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 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 
 
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not 
be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a 
daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/mL (5 %) 
solution for infusion given over 30 minutes (see section 6.6 for instructions on dilution). 
 
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 randomised clinical trials, a subcutaneous dose of 23 MIU 
(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 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 to 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. 
 
In patients treated with myeloablative therapy followed by bone marrow transplantation 
 
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or 
24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous 
infusion. Filgrastim should be diluted in 20 mL of glucose 50 mg/mL (5 %) solution for infusion (see 
section 6.6 for instructions on dilution). 
 
The first dose of filgrastim should not be administered less than 24 hours following cytotoxic 
chemotherapy and within 24 hours of bone marrow infusion. 
 
Once the neutrophil nadir has been passed the daily dose 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 MIU (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 
 

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For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy 
followed by autologous peripheral blood progenitor cell transplantation 
 
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU 
(10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection 
for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 mL of glucose 50 mg/mL 
(5 %) solution for infusion (see section 6.6 for instructions on dilution). 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 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of 
chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to 
the normal range. Leukapheresis should be performed during the period when the ANC rises from 
< 0.5 x 109/L to > 5.0 x 109/L. For patients who have not had extensive chemotherapy, one 
leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended. 
 
For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell 
transplantation 
 
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU 
(10 μg)/kg/day subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 
and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipient bodyweight. 
 
In patients with severe chronic neutropenia (SCN) 
 
Congenital neutropenia 
The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in 
divided doses. 
 
Idiopathic or cyclic neutropenia 
The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously 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 
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 to 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 
of ≤ 2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU 
(24 μg)/kg/day in patients with SCN has not been established. 
 
In patients with HIV infection 
 
For reversal of neutropenia 
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous 
injection with titration up to a maximum of 0.4 MIU (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 MIU (10 μg)/kg/day were required to achieve 
reversal of neutropenia. 

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For maintaining normal neutrophil counts 
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal 
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU 
(300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary, 
as determined by the patient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical 
studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC 
> 2.0 x 109/L, with the median dose frequency being 3 days per week. Long-term administration may 
be required to maintain the ANC > 2.0 x 109/L. 
 
Special populations 
 
Elderly patients 
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. 
 
Patients with renal or 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 use in the SCN and cancer settings 
Sixty-five percent of the patients studied in the SCN trial programme 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 severe 
chronic neutropenia. 
 
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 
 
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established 
dosage regimens (see below). 
 
Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman's 
syndrome) with abnormal cytogenetics (see below). 
 
Special precautions in patients with acute myeloid leukaemia 
 
Malignant cell growth 
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar 
effects may also be seen on some non-myeloid cells in vitro. 
 
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or 
chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for 

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use in these conditions. Particular care should be taken to distinguish the diagnosis of blast 
transformation of chronic myeloid leukaemia from acute myeloid leukaemia. 
 
In view of limited safety and efficacy data in patients with secondary AML, 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. 
 
Other special precautions 
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. 
 
Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after 
G-CSF administration. Patients with a recent history of pulmonary 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 Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued 
and appropriate treatment given in these cases. 
 
Capillary leak syndrome has been reported after G-CSF administration and is characterised by 
hypotension, hypoalbuminaemia, oedema and haemoconcentration. 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). 
 
Special precautions in cancer patients 
 
Leukocytosis 
White blood cell counts of 100 x 109/L or greater have been observed in less than 5 % of patients 
receiving filgrastim at doses above 0.3 MIU/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. However, during the period of administration of filgrastim for 
PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Risks associated with increased doses of chemotherapy 
Special caution should be used when treating patients with high dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may 
lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please 
refer to the Summary of Product Characteristics of the specific chemotherapy agents used). 
 
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 

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counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such 
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 
by tumour). 
 
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving 
G-CSF after allogeneic bone marrow transplantation (see section 5.1). 
 
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been 
associated with transient positive bone-imaging findings. This should be considered when interpreting 
bone-imaging results. 
 
Special precautions in patients undergoing peripheral blood progenitor cell 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. 
 
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 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 
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 106 CD34+ cells/kg is based on published 
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield 
appear to correlate with more rapid recovery, those below with slower recovery. 
 
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. 
 

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PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory 
eligibility criteria for stem cell donation. Particular attention should be paid to haematological values 
and infectious diseases. 
 
The safety and efficacy of filgrastim have not been assessed in normal donors < 16 years or 
> 60 years. 
 
Transient thrombocytopenia (platelets < 100 x 109/L) following filgrastim administration and 
leukapheresis was observed in 35 % of subjects studied. Among these, two cases of platelets 
< 50 x 109/L were reported and attributed to the leukapheresis procedure. 
 
If more than one leukapheresis is required, particular attention should be paid to donors with platelets 
< 100 x 109/L prior to leukapheresis; in general apheresis should not be performed if platelets 
< 75 x 109/L. 
 
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 
in haemostasis. 
 
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices 
return to normal. 
 
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The 
significance of these changes in terms of the development of haematological malignancy is unknown. 
Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant myeloid clone 
can not be excluded. It is recommended that the apheresis centre perform a systematic record and 
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 
 
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of 
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical 
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or 
patients reporting left upper abdominal pain or shoulder tip pain. 
 
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, 
dyspnoea and hypoxia) have been reported very rarely in postmarketing experience. In case of 
suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should 
be considered and appropriate medical care given. 
 
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 
 
Blood cell counts 
Platelet counts should be monitored closely, especially during the first few weeks of filgrastim 
therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in 
patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm3. 
 
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 
which require close monitoring of cell counts. 

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Transformation to leukaemia or myelodysplastic syndrome 
Special care should be taken in the diagnosis of severe chronic neutropenias 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. If patients with SCN develop abnormal 
cytogenetics, the risks and benefits of continuing filgrastim should be carefully weighed; filgrastim 
should be discontinued if MDS or leukaemia occur. 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. 
 
Splenic enlargement is a direct effect of treatment with filgrastim. Thirty-one percent (31 %) of 
patients in studies were documented as having palpable splenomegaly. Increases in volume, measured 
radiographically, occurred early during filgrastim therapy and tended to plateau. Dose reductions were 
noted to slow or stop the progression of splenic enlargement and in 3 % of patients a splenectomy was 
required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to 
detect abnormal increases in splenic volume. 
 
Haematuria/proteinuria occurred in a small number of patients. Regular urinanalysis 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 MIU (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 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). 
 

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Infections and malignancies causing myelosuppression 
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium 
avium complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating 
infections or malignancy, consider appropriate therapy for treatment of the underlying condition in 
addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on 
neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established. 
 
Special precautions in sickle cell disease 
 
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with 
sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in 
patients with sickle cell disease and only after careful evaluation of the potential risks and benefits. 
 
Excipients 
 
Biograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not 
use this medicinal product. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. 
essentially ‘sodium-free’. 
 
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, 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 adequate data from the use of filgrastim in pregnant women. There are reports in the 
literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. 
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is 
unknown. Filgrastim should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk 
has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to 
continue/discontinue therapy with filgrastim should be made taking into account the benefit of 
breast-feeding to the child and the benefit of filgrastim therapy to the woman. 
 
4.7 Effects on ability to drive and use machines 
 
Filgrastim has minor or moderate influence on the ability to drive and use machines. If the patient is 
experiencing fatigue, caution is advised when driving a car or operating machines. 
 

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4.8 Undesirable effects 
 
Summary of the safety profile 
 
During clinical studies 541 cancer patients and 188 healthy volunteers were exposed to Biograstim. 
The safety profile of Biograstim observed in these clinical studies was consistent with that reported 
with the reference product used in these studies. 
 
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported 
uncommonly (≥ 1/1000 to < 1/100) in cancer patients undergoing chemotherapy and healthy donors 
undergoing peripheral blood progenitor cell mobilisation following administration of G-CSFs; see 
section 4.4 and subsection “Description of selected adverse reactions” of section 4.8. 
 
The following undesirable effects and their frequencies have been observed under treatment with 
filgrastim based on published information. 
 
The assessment of undesirable effects is based on the following frequency data: 
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 
Not known:  cannot be estimated from the available data 
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
In cancer patients 
 
In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended 
dose were mild or moderate musculoskeletal pain, occurring in 10 %, and severe musculoskeletal pain 
in 3 % of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent 
undesirable effects include urinary abnormalities predominantly mild or moderate dysuria. 
 
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of 
undesirable effects associated with cytotoxic chemotherapy. Undesirable effects reported with equal 
frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included 
nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, headache, cough, skin rash, 
chest pain, generalised weakness, sore throat, constipation and unspecified pain. 
 
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase (LDH), 
alkaline phosphatase, serum uric acid and gamma-glutamyltransferase (GGT) occurred with filgrastim 
in approximately 50 %, 35 %, 25 %, and 10 % of patients respectively, at recommended doses. 
 
Transient decreases in blood pressure, not requiring clinical treatment, have been reported 
occasionally. 
 
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see section 5.1). 
 
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 
reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone 
marrow transplantation. The causal association with filgrastim has not been established. 
 
Very rare events of cutaneous vasculitis have been reported in patients treated with filgrastim. The 
mechanism of vasculitis in patients receiving filgrastim is unknown. 
 

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The occurrence of Sweet's syndrome (acute febrile dermatosis) has been reported occasionally. 
However, since a significant percentage of these patients were suffering from leukaemia, a condition 
known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been 
established. 
 
Exacerbation of rheumatoid arthritis has been observed in individual cases. 
 
Pseudogout has been reported in patients with cancer treated with filgrastim. 
 
Rare pulmonary undesirable effects including interstitial pneumonia, pulmonary oedema and 
pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or adult 
respiratory distress syndrome (ARDS) which may be fatal (see section 4.4). 
 
Allergic Reactions: Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema, 
dyspnoea and hypotension, occurring on initial or subsequent treatment, have been reported in 
patients receiving filgrastim. 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. 
 
Isolated cases of sickle cells crises have been reported in patients with sickle cell disease (see 
section 4.4). 
 
System organ class Frequency Undesirable effect 
Metabolism and nutrition 
disorders 

Very common Elevated alkaline phosphatase, 
elevated LDH, elevated uric 
acid 

Nervous system disorders Common Headache 
Vascular disorders Rare Vascular disorder 

Uncommon Capillary leak syndrome* 
Respiratory, thoracic and 
mediastinal disorders 

Common Cough, sore throat 
Very rare Pulmonary infiltrates 

Gastrointestinal disorders Very common Nausea/Vomiting 
Common Constipation, anorexia, 

diarrhoea, mucositis 
Hepatobiliary disorders Very common Elevated GGT 
Skin and subcutaneous tissue 
disorders 

Common Alopecia, skin rash 
Very rare Sweet's syndrome, cutaneous 

vasculitis 
Musculoskeletal and connective 
tissue disorders 

Very common Chest pain, musculoskeletal 
pain 

Very rare Rheumatoid arthritis 
exacerbation 

Renal and urinary disorders Very rare Urinary abnormalities 
General disorders and 
administration site conditions 

Common Fatigue, generalised weakness 
Uncommon Unspecified pain 
Very rare Allergic reaction 

*See subsection “Description of selected adverse reactions” of section 4.8 
 
In peripheral blood progenitor cell mobilisation in normal donors 
 
The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal 
pain. Leukocytosis (WBC > 50 x 109/L) was observed in 41 % of donors and transient 
thrombocytopenia (platelets < 100 x 109/L) following filgrastim and leukapheresis was observed in 
35 % of donors. 
 

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Transient, minor increases in alkaline phosphatase, LDH, SGOT (serum glutamic oxaloacetic 
transaminase) and uric acid have been reported in normal donors receiving filgrastim; these were 
without clinical sequelae. 
 
Exacerbation of arthritic symptoms has been observed very rarely. 
 
Symptoms suggestive of severe allergic reactions have been reported very rarely. 
 
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies. 
 
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs (see 
section 4.4). 
 
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration, 
dyspnoea and hypoxia) have been reported in postmarketing experience (see section 4.4). 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Very common Leukocytosis, thrombocytopenia 
Uncommon Spleen disorder 

Metabolism and nutrition 
disorders 

Common Elevated alkaline phosphatase, 
elevated LDH 

Uncommon SGOT increased, 
hyperuricaemia 

Nervous system disorders Very common Headache 
Vascular disorders Uncommon Capillary leak syndrome* 
Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 
Uncommon Rheumatoid arthritis 

exacerbation 
General disorders and 
administration site conditions 

Uncommon Severe allergic reaction 

*See subsection “Description of selected adverse reactions” of section 4.8 
 
In SCN patients 
 
Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some 
their frequencies tend to decrease with time. 
 
The most frequent undesirable effects attributable to filgrastim were bone pain, and general 
musculoskeletal pain. 
 
Other undesirable effects seen include splenic enlargement, which may be progressive in a minority of 
cases and thrombocytopenia. Headache and diarrhoea have been reported shortly after starting 
filgrastim therapy, typically in less than 10 % of patients. Anaemia and epistaxis have also been 
reported. 
 
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase 
and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been 
seen. 
 
Undesirable effects possibly related to filgrastim therapy and typically occurring in < 2 % of SCN 
patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and 
rash. 
 

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During long term use, cutaneous vasculitis has been reported in 2 % of SCN patients. There have been 
very few instances of proteinuria/haematuria. 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Very common Anaemia, splenomegaly 
Common Thrombocytopenia 
Uncommon Spleen disorder 

Metabolism and nutrition 
disorders 

Very common Decreased glucose, elevated 
alkaline phosphatase, elevated 
LDH, hyperuricaemia 

Nervous system disorders Common Headache 
Respiratory, thoracic and 
mediastinal disorders 

Very common Epistaxis 

Gastrointestinal disorders Common Diarrhoea 
Hepatobiliary disorders Common Hepatomegaly 
Skin and subcutaneous tissue 
disorders 

Common Alopecia, cutaneous vasculitis, 
injection site pain, rash 

Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 
Common Osteoporosis 

Renal and urinary disorders Uncommon Haematuria, proteinuria 
 
In patients with HIV 
 
In clinical studies, the only undesirable effects that were consistently considered to be related to 
filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and 
myalgia. The incidence of these events was similar to that reported in cancer patients. 
 
Splenic enlargement was reported to be related to filgrastim therapy in < 3 % of patients. In all cases 
this was mild or moderate on physical examination and the clinical course was benign; no patients had 
a diagnosis of hypersplenism and no patients underwent splenectomy. As splenic enlargement is a 
common finding in patients with HIV infection and is present to varying degrees in most patients with 
AIDS, the relationship to filgrastim treatment is unclear. 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Common Spleen disorder 

Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 

 
Description of selected adverse reactions 
 
Cases of capillary leak syndrome have been reported in the postmarketing setting with G-CSF use. 
These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple 
chemotherapy medications or undergoing apheresis (see section 4.4). 
 
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 
 
No case of overdose has been reported. 

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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 
 
Biograstim 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. Biograstim 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 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 
accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and 
the need for platelet transfusions. 
 
Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid 
haematological recovery, leading to a significant decrease in time to unsupported platelet recovery, 
when compared with allogeneic bone marrow transplantation. 
 
One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow 
transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment 
related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective 
international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk 
of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including 
the results of nine prospective randomized trials, 8 retrospective studies and 1 case-controlled study, 
did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related 
mortality. 
 

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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) 

aAnalysis includes studies involving bone marrow transplant during this period; some studies used 
GM-CSF (granulocyte-macrophage–colony stimulating factor) 
bAnalysis includes patients receiving bone marrow transplant during this period 
 
Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normal 
donors allows a collection of 4 x 106 CD34+ cells/kg recipient body weight in the majority of the 
donors after two leukaphereses. Normal donors are given a dose of a 10 μg/kg/day, administered 
subcutaneously for 4 to 5 consecutive days. 
 
Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic 
neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a 
reduction of infection and related events. 
 
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow 
scheduled dosing of antiviral and/or other myelosuppressive medicinal product. 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. 
 
The efficacy and safety of Biograstim has been assessed in randomised, controlled phase III studies in 
breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences between 
Biograstim and the reference product with regard to duration of severe neutropenia and incidence of 
febrile neutropenia. 
 
5.2 Pharmacokinetic properties 
 
Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the 
pharmacokinetic profile of Biograstim was comparable to that of the reference product after 
subcutaneous and intravenous administration. 
 
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both 
subcutaneous and intravenous administration. The serum elimination half-life of filgrastim is 
approximately 3.5 hours, with a clearance rate of approximately 0.6 mL/min/kg. Continuous infusion 
with filgrastim over a period of up to 28 days, in patients recovering from autologous bone-marrow 
transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives. 
There is a positive linear correlation between the dose and the serum concentration of filgrastim, 
whether administered intravenously or subcutaneously. Following subcutaneous administration of 
recommended doses, serum concentrations were maintained above 10 ng/mL for 8 to 16 hours. The 
volume of distribution in blood is approximately 150 mL/kg. 
 
In cancer patients, the pharmacokinetic profile of Biograstim and the reference product was 
comparable after single and repeated subcutaneous administration. 

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5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, genotoxicity and local tolerance. 
 
Preclinical data from conventional studies of repeated dose toxicity revealed the expected 
pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, 
extramedullary haematopoiesis and splenic enlargement. 
 
No effect was observed on the fertility of male and female rats or gestation in rats. There is no 
evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of 
embryo-loss has been observed in rabbits, but no malformation has been seen. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Acetic acid, glacial 
Sodium hydroxide 
Sorbitol (E420) 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Biograstim should 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 except diluted, as mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
30 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). 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I glass pre-filled syringe with a permanently attached stainless steel needle with or without 
safety device to prevent needle stick injury and re-use. 
 

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Packs containing 1, 5 or 10 pre-filled syringes with 0.5 mL solution or multipacks containing 10 (2 
packs of 5) pre-filled syringes with 0.5 mL solution. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
If required, Biograstim may be diluted in glucose 50 mg/mL (5 %) solution for infusion. 
 
Dilution to a final concentration less than 0.2 MIU (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 MIU (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 MIU (300 μg) 
should be given with 0.2 mL of 200 mg/mL (20 %) human albumin solution added. 
 
When diluted in glucose 50 mg/mL (5 %) solution for infusion, Biograstim is compatible with glass 
and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) 
and polypropylene. 
 
Biograstim does not contain any preservative. In view of the possible risk of microbial contamination, 
Biograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Biograstim. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/001 
EU/1/08/450/002 
EU/1/08/450/003 
EU/1/08/450/004 
EU/1/08/450/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 September 2008. 
Date of latest renewal: 25 July 2013. 
 
 

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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/. 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of solution for injection or infusion contains 60 million international units [MIU] (600 µg) 
of filgrastim. 
 
Each pre-filled syringe contains 48 MIU (480 µg) of filgrastim in 0.8 mL solution for injection or 
infusion. 
 
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced in 
Escherichia coli K802 by recombinant DNA technology. 
 
Excipient with known effect 
Each mL of solution contains 50 mg of sorbitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection or infusion 
 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Biograstim 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 filgrastim are similar in adults and children receiving cytotoxic chemotherapy. 
 
Biograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC). 
 
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 Biograstim is indicated to increase neutrophil counts and to reduce the 
incidence and duration of infection-related events. 
 
Biograstim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 
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. 
 
4.2 Posology and method of administration 
 

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Special requirements 
 
Filgrastim 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 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 
 
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not 
be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a 
daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/mL (5 %) 
solution for infusion given over 30 minutes (see section 6.6 for instructions on dilution). 
 
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 randomised clinical trials, a subcutaneous dose of 23 MIU 
(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 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 to 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. 
 
In patients treated with myeloablative therapy followed by bone marrow transplantation 
 
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or 
24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous 
infusion. Filgrastim should be diluted in 20 mL of glucose 50 mg/mL (5 %) solution for infusion (see 
section 6.6 for instructions on dilution). 
 
The first dose of filgrastim should not be administered less than 24 hours following cytotoxic 
chemotherapy and within 24 hours of bone marrow infusion. 
 
Once the neutrophil nadir has been passed the daily dose 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 MIU (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 
 

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For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy 
followed by autologous peripheral blood progenitor cell transplantation 
 
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU 
(10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection 
for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 mL of glucose 50 mg/mL 
(5 %) solution for infusion (see section 6.6 for instructions on dilution). 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 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of 
chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to 
the normal range. Leukapheresis should be performed during the period when the ANC rises from 
< 0.5 x 109/L to > 5.0 x 109/L. For patients who have not had extensive chemotherapy, one 
leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended. 
 
For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell 
transplantation 
 
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU 
(10 μg)/kg/day subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 
and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipient bodyweight. 
 
In patients with severe chronic neutropenia (SCN) 
 
Congenital neutropenia 
The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in 
divided doses. 
 
Idiopathic or cyclic neutropenia 
The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously 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 
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 to 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 
of ≤ 2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU 
(24 μg)/kg/day in patients with SCN has not been established. 
 
In patients with HIV infection 
 
For reversal of neutropenia 
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous 
injection with titration up to a maximum of 0.4 MIU (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 MIU (10 μg)/kg/day were required to achieve 
reversal of neutropenia. 

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For maintaining normal neutrophil counts 
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal 
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU 
(300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary, 
as determined by the patient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical 
studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC 
> 2.0 x 109/L, with the median dose frequency being 3 days per week. Long-term administration may 
be required to maintain the ANC > 2.0 x 109/L. 
 
Special populations 
 
Elderly patients 
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. 
 
Patients with renal or 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 use in the SCN and cancer settings 
Sixty-five percent of the patients studied in the SCN trial programme 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 severe 
chronic neutropenia. 
 
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 
 
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established 
dosage regimens (see below). 
 
Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman's 
syndrome) with abnormal cytogenetics (see below). 
 
Special precautions in patients with acute myeloid leukaemia 
 
Malignant cell growth 
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar 
effects may also be seen on some non-myeloid cells in vitro. 
 
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or 
chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for 

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use in these conditions. Particular care should be taken to distinguish the diagnosis of blast 
transformation of chronic myeloid leukaemia from acute myeloid leukaemia. 
 
In view of limited safety and efficacy data in patients with secondary AML, 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. 
 
Other special precautions 
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. 
 
Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after 
G-CSF administration. Patients with a recent history of pulmonary 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 Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued 
and appropriate treatment given in these cases. 
 
Capillary leak syndrome has been reported after G-CSF administration and is characterised by 
hypotension, hypoalbuminaemia, oedema and haemoconcentration. 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). 
 
Special precautions in cancer patients 
 
Leukocytosis 
White blood cell counts of 100 x 109/L or greater have been observed in less than 5 % of patients 
receiving filgrastim at doses above 0.3 MIU/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. However, during the period of administration of filgrastim for 
PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Risks associated with increased doses of chemotherapy 
Special caution should be used when treating patients with high dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may 
lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please 
refer to the Summary of Product Characteristics of the specific chemotherapy agents used). 
 
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 

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counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such 
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 
by tumour). 
 
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving 
G-CSF after allogeneic bone marrow transplantation (see section 5.1). 
 
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been 
associated with transient positive bone-imaging findings. This should be considered when interpreting 
bone-imaging results. 
 
Special precautions in patients undergoing peripheral blood progenitor cell 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. 
 
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 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 
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 106 CD34+ cells/kg is based on published 
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield 
appear to correlate with more rapid recovery, those below with slower recovery. 
 
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. 
 

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PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory 
eligibility criteria for stem cell donation. Particular attention should be paid to haematological values 
and infectious diseases. 
 
The safety and efficacy of filgrastim have not been assessed in normal donors < 16 years or 
> 60 years. 
 
Transient thrombocytopenia (platelets < 100 x 109/L) following filgrastim administration and 
leukapheresis was observed in 35 % of subjects studied. Among these, two cases of platelets 
< 50 x 109/L were reported and attributed to the leukapheresis procedure. 
 
If more than one leukapheresis is required, particular attention should be paid to donors with platelets 
< 100 x 109/L prior to leukapheresis; in general apheresis should not be performed if platelets 
< 75 x 109/L. 
 
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 
in haemostasis. 
 
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices 
return to normal. 
 
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The 
significance of these changes in terms of the development of haematological malignancy is unknown. 
Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant myeloid clone 
can not be excluded. It is recommended that the apheresis centre perform a systematic record and 
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 
 
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of 
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical 
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or 
patients reporting left upper abdominal pain or shoulder tip pain. 
 
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, 
dyspnoea and hypoxia) have been reported very rarely in postmarketing experience. In case of 
suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should 
be considered and appropriate medical care given. 
 
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 
 
Blood cell counts 
Platelet counts should be monitored closely, especially during the first few weeks of filgrastim 
therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in 
patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm3. 
 
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 
which require close monitoring of cell counts. 

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Transformation to leukaemia or myelodysplastic syndrome 
Special care should be taken in the diagnosis of severe chronic neutropenias 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. If patients with SCN develop abnormal 
cytogenetics, the risks and benefits of continuing filgrastim should be carefully weighed; filgrastim 
should be discontinued if MDS or leukaemia occur. 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. 
 
Splenic enlargement is a direct effect of treatment with filgrastim. Thirty-one percent (31 %) of 
patients in studies were documented as having palpable splenomegaly. Increases in volume, measured 
radiographically, occurred early during filgrastim therapy and tended to plateau. Dose reductions were 
noted to slow or stop the progression of splenic enlargement and in 3 % of patients a splenectomy was 
required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to 
detect abnormal increases in splenic volume. 
 
Haematuria/proteinuria occurred in a small number of patients. Regular urinanalysis 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 MIU (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 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). 
 

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Infections and malignancies causing myelosuppression 
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium 
avium complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating 
infections or malignancy, consider appropriate therapy for treatment of the underlying condition in 
addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on 
neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established. 
 
Special precautions in sickle cell disease 
 
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with 
sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in 
patients with sickle cell disease and only after careful evaluation of the potential risks and benefits. 
 
Excipients 
 
Biograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not 
use this medicinal product. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. 
essentially ‘sodium-free’. 
 
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, 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 adequate data from the use of filgrastim in pregnant women. There are reports in the 
literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. 
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is 
unknown. Filgrastim should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk 
has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to 
continue/discontinue therapy with filgrastim should be made taking into account the benefit of 
breast-feeding to the child and the benefit of filgrastim therapy to the woman. 
 
4.7 Effects on ability to drive and use machines 
 
Filgrastim has minor or moderate influence on the ability to drive and use machines. If the patient is 
experiencing fatigue, caution is advised when driving a car or operating machines. 
 

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4.8 Undesirable effects 
 
Summary of the safety profile 
 
During clinical studies 541 cancer patients and 188 healthy volunteers were exposed to Biograstim. 
The safety profile of Biograstim observed in these clinical studies was consistent with that reported 
with the reference product used in these studies. 
 
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported 
uncommonly (≥ 1/1000 to < 1/100) in cancer patients undergoing chemotherapy and healthy donors 
undergoing peripheral blood progenitor cell mobilisation following administration of G-CSFs; see 
section 4.4 and subsection “Description of selected adverse reactions” of section 4.8. 
 
The following undesirable effects and their frequencies have been observed under treatment with 
filgrastim based on published information. 
 
The assessment of undesirable effects is based on the following frequency data: 
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 
Not known:  cannot be estimated from the available data 
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
In cancer patients 
 
In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended 
dose were mild or moderate musculoskeletal pain, occurring in 10 %, and severe musculoskeletal pain 
in 3 % of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent 
undesirable effects include urinary abnormalities predominantly mild or moderate dysuria. 
 
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of 
undesirable effects associated with cytotoxic chemotherapy. Undesirable effects reported with equal 
frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included 
nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, headache, cough, skin rash, 
chest pain, generalised weakness, sore throat, constipation and unspecified pain. 
 
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase (LDH), 
alkaline phosphatase, serum uric acid and gamma-glutamyltransferase (GGT) occurred with filgrastim 
in approximately 50 %, 35 %, 25 %, and 10 % of patients respectively, at recommended doses. 
 
Transient decreases in blood pressure, not requiring clinical treatment, have been reported 
occasionally. 
 
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see section 5.1). 
 
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 
reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone 
marrow transplantation. The causal association with filgrastim has not been established. 
 
Very rare events of cutaneous vasculitis have been reported in patients treated with filgrastim. The 
mechanism of vasculitis in patients receiving filgrastim is unknown. 
 

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The occurrence of Sweet's syndrome (acute febrile dermatosis) has been reported occasionally. 
However, since a significant percentage of these patients were suffering from leukaemia, a condition 
known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been 
established. 
 
Exacerbation of rheumatoid arthritis has been observed in individual cases. 
 
Pseudogout has been reported in patients with cancer treated with filgrastim. 
 
Rare pulmonary undesirable effects including interstitial pneumonia, pulmonary oedema and 
pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or adult 
respiratory distress syndrome (ARDS) which may be fatal (see section 4.4). 
 
Allergic Reactions: Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema, 
dyspnoea and hypotension, occurring on initial or subsequent treatment, have been reported in 
patients receiving filgrastim. 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. 
 
Isolated cases of sickle cells crises have been reported in patients with sickle cell disease (see 
section 4.4). 
 
System organ class Frequency Undesirable effect 
Metabolism and nutrition 
disorders 

Very common Elevated alkaline phosphatase, 
elevated LDH, elevated uric 
acid 

Nervous system disorders Common Headache 
Vascular disorders Rare Vascular disorder 

Uncommon Capillary leak syndrome* 
Respiratory, thoracic and 
mediastinal disorders 

Common Cough, sore throat 
Very rare Pulmonary infiltrates 

Gastrointestinal disorders Very common Nausea/Vomiting 
Common Constipation, anorexia, 

diarrhoea, mucositis 
Hepatobiliary disorders Very common Elevated GGT 
Skin and subcutaneous tissue 
disorders 

Common Alopecia, skin rash 
Very rare Sweet's syndrome, cutaneous 

vasculitis 
Musculoskeletal and connective 
tissue disorders 

Very common Chest pain, musculoskeletal 
pain 

Very rare Rheumatoid arthritis 
exacerbation 

Renal and urinary disorders Very rare Urinary abnormalities 
General disorders and 
administration site conditions 

Common Fatigue, generalised weakness 
Uncommon Unspecified pain 
Very rare Allergic reaction 

*See subsection “Description of selected adverse reactions” of section 4.8 
 
In peripheral blood progenitor cell mobilisation in normal donors 
 
The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal 
pain. Leukocytosis (WBC > 50 x 109/L) was observed in 41 % of donors and transient 
thrombocytopenia (platelets < 100 x 109/L) following filgrastim and leukapheresis was observed in 
35 % of donors. 
 

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Transient, minor increases in alkaline phosphatase, LDH, SGOT (serum glutamic oxaloacetic 
transaminase) and uric acid have been reported in normal donors receiving filgrastim; these were 
without clinical sequelae. 
 
Exacerbation of arthritic symptoms has been observed very rarely. 
 
Symptoms suggestive of severe allergic reactions have been reported very rarely. 
 
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies. 
 
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs (see 
section 4.4). 
 
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration, 
dyspnoea and hypoxia) have been reported in postmarketing experience (see section 4.4). 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Very common Leukocytosis, thrombocytopenia 
Uncommon Spleen disorder 

Metabolism and nutrition 
disorders 

Common Elevated alkaline phosphatase, 
elevated LDH 

Uncommon SGOT increased, 
hyperuricaemia 

Nervous system disorders Very common Headache 
Vascular disorders Uncommon Capillary leak syndrome* 
Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 
Uncommon Rheumatoid arthritis 

exacerbation 
General disorders and 
administration site conditions 

Uncommon Severe allergic reaction 

*See subsection “Description of selected adverse reactions” of section 4.8 
 
In SCN patients 
 
Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some 
their frequencies tend to decrease with time. 
 
The most frequent undesirable effects attributable to filgrastim were bone pain, and general 
musculoskeletal pain. 
 
Other undesirable effects seen include splenic enlargement, which may be progressive in a minority of 
cases and thrombocytopenia. Headache and diarrhoea have been reported shortly after starting 
filgrastim therapy, typically in less than 10 % of patients. Anaemia and epistaxis have also been 
reported. 
 
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase 
and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been 
seen. 
 
Undesirable effects possibly related to filgrastim therapy and typically occurring in < 2 % of SCN 
patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and 
rash. 
 

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During long term use, cutaneous vasculitis has been reported in 2 % of SCN patients. There have been 
very few instances of proteinuria/haematuria. 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Very common Anaemia, splenomegaly 
Common Thrombocytopenia 
Uncommon Spleen disorder 

Metabolism and nutrition 
disorders 

Very common Decreased glucose, elevated 
alkaline phosphatase, elevated 
LDH, hyperuricaemia 

Nervous system disorders Common Headache 
Respiratory, thoracic and 
mediastinal disorders 

Very common Epistaxis 

Gastrointestinal disorders Common Diarrhoea 
Hepatobiliary disorders Common Hepatomegaly 
Skin and subcutaneous tissue 
disorders 

Common Alopecia, cutaneous vasculitis, 
injection site pain, rash 

Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 
Common Osteoporosis 

Renal and urinary disorders Uncommon Haematuria, proteinuria 
 
In patients with HIV 
 
In clinical studies, the only undesirable effects that were consistently considered to be related to 
filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and 
myalgia. The incidence of these events was similar to that reported in cancer patients. 
 
Splenic enlargement was reported to be related to filgrastim therapy in < 3 % of patients. In all cases 
this was mild or moderate on physical examination and the clinical course was benign; no patients had 
a diagnosis of hypersplenism and no patients underwent splenectomy. As splenic enlargement is a 
common finding in patients with HIV infection and is present to varying degrees in most patients with 
AIDS, the relationship to filgrastim treatment is unclear. 
 
System organ class Frequency Undesirable effect 
Blood and lymphatic system 
disorders 

Common Spleen disorder 

Musculoskeletal and connective 
tissue disorders 

Very common Musculoskeletal pain 

 
Description of selected adverse reactions 
 
Cases of capillary leak syndrome have been reported in the postmarketing setting with G-CSF use. 
These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple 
chemotherapy medications or undergoing apheresis (see section 4.4). 
 
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 
 
No case of overdose has been reported. 

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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 
 
Biograstim 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. Biograstim 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 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 
accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and 
the need for platelet transfusions. 
 
Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid 
haematological recovery, leading to a significant decrease in time to unsupported platelet recovery, 
when compared with allogeneic bone marrow transplantation. 
 
One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow 
transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment 
related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective 
international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk 
of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including 
the results of nine prospective randomized trials, 8 retrospective studies and 1 case-controlled study, 
did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related 
mortality. 
 

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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) 

aAnalysis includes studies involving bone marrow transplant during this period; some studies used 
GM-CSF (granulocyte-macrophage–colony stimulating factor) 
bAnalysis includes patients receiving bone marrow transplant during this period 
 
Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normal 
donors allows a collection of 4 x 106 CD34+ cells/kg recipient body weight in the majority of the 
donors after two leukaphereses. Normal donors are given a dose of a 10 μg/kg/day, administered 
subcutaneously for 4 to 5 consecutive days. 
 
Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic 
neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a 
reduction of infection and related events. 
 
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow 
scheduled dosing of antiviral and/or other myelosuppressive medicinal product. 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. 
 
The efficacy and safety of Biograstim has been assessed in randomised, controlled phase III studies in 
breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences between 
Biograstim and the reference product with regard to duration of severe neutropenia and incidence of 
febrile neutropenia. 
 
5.2 Pharmacokinetic properties 
 
Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the 
pharmacokinetic profile of Biograstim was comparable to that of the reference product after 
subcutaneous and intravenous administration. 
 
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both 
subcutaneous and intravenous administration. The serum elimination half-life of filgrastim is 
approximately 3.5 hours, with a clearance rate of approximately 0.6 mL/min/kg. Continuous infusion 
with filgrastim over a period of up to 28 days, in patients recovering from autologous bone-marrow 
transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives. 
There is a positive linear correlation between the dose and the serum concentration of filgrastim, 
whether administered intravenously or subcutaneously. Following subcutaneous administration of 
recommended doses, serum concentrations were maintained above 10 ng/mL for 8 to 16 hours. The 
volume of distribution in blood is approximately 150 mL/kg. 
 
In cancer patients, the pharmacokinetic profile of Biograstim and the reference product was 
comparable after single and repeated subcutaneous administration. 

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35 

 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, genotoxicity and local tolerance. 
 
Preclinical data from conventional studies of repeated dose toxicity revealed the expected 
pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, 
extramedullary haematopoiesis and splenic enlargement. 
 
No effect was observed on the fertility of male and female rats or gestation in rats. There is no 
evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of 
embryo-loss has been observed in rabbits, but no malformation has been seen. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Acetic acid, glacial 
Sodium hydroxide 
Sorbitol (E420) 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Biograstim should 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 except diluted, as mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
30 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). 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I glass pre-filled syringe with a permanently attached stainless steel needle with or without 
safety device to prevent needle stick injury and re-use. 
 

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36 

Packs containing 1, 5 or 10 pre-filled syringes with 0.8 mL solution or multipacks containing 10 (2 
packs of 5) pre-filled syringes with 0.8 mL solution. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
If required, Biograstim may be diluted in glucose 50 mg/mL (5 %) solution for infusion. 
 
Dilution to a final concentration less than 0.2 MIU (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 MIU (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 MIU (300 μg) 
should be given with 0.2 mL of 200 mg/mL (20 %) human albumin solution added. 
 
When diluted in glucose 50 mg/mL (5 %) solution for infusion, Biograstim is compatible with glass 
and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) 
and polypropylene. 
 
Biograstim does not contain any preservative. In view of the possible risk of microbial contamination, 
Biograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Biograstim. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/005 
EU/1/08/450/006 
EU/1/08/450/007 
EU/1/08/450/008 
EU/1/08/450/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 September 2008. 
Date of latest renewal: 25 July 2013. 
 
 

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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/. 

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ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER 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 

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
SICOR Biotech UAB 
Molėtų pl. 5  
08409 Vilnius 
Lithuania 
 
Name and address of the manufacturer responsible for batch release 
 
Merckle Biotec GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
 
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 marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and 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. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 

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40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 30 MIU/0.5 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in 
0.5 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
1 pre-filled syringe containing 0.5 mL 
5 pre-filled syringes containing 0.5 mL 
5 pre-filled syringes with safety device containing 0.5 mL 
10 pre-filled syringes containing 0.5 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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8. EXPIRY DATE 
 
EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/001 1 pre-filled syringe 
EU/1/08/450/002 5 pre-filled syringes 
EU/1/08/450/004 10 pre-filled syringes 
EU/1/08/450/009 5 pre-filled syringes with safety device 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Biograstim 30 MIU/0.5 mL 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in 
0.8 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
1 pre-filled syringe containing 0.8 mL 
5 pre-filled syringes containing 0.8 mL 
5 pre-filled syringes with safety device containing 0.8 mL 
10 pre-filled syringes containing 0.8 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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8. EXPIRY DATE 
 
EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/005 1 pre-filled syringe 
EU/1/08/450/006 5 pre-filled syringes 
EU/1/08/450/008 10 pre-filled syringes 
EU/1/08/450/010 5 pre-filled syringes with safety device 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Biograstim 48 MIU/0.8 mL 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Wrapper Label on Multipacks With Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 30 MIU/0.5 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in 
0.5 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
Multipack: 10 (2 packs of 5) pre-filled syringes containing 0.5 mL. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/003 2 x 5 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Wrapper Label on Multipacks With Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in 
0.8 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
Multipack: 10 (2 packs of 5) pre-filled syringes containing 0.8 mL. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/007 2 x 5 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
Multipack Carton - Without Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 30 MIU/0.5 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in 
0.5 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
5 pre-filled syringes containing 0.5 mL. Component of a multipack, cannot be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/003 2 x 5 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Biograstim 30 MIU/0.5 mL 
 
 

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PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
Multipack Carton - Without Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 
 
Filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in 
0.8 mL (60 MIU/mL, 600 microgram/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read 
the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection or infusion 
 
5 pre-filled syringes containing 0.8 mL. Component of a multipack, cannot be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use and intravenous use. 
 
For single use only. 
 
Please use as follows: 
Box for the prescribed dose 
 
 
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 

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EXP 
 
After dilution use within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/450/007 2 x 5 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Biograstim 48 MIU/0.8 mL 
 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Biograstim 30 MIU/0.5 mL solution for injection or infusion 
 
Filgrastim 
 
SC 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 mL 
 
 
6. OTHER 
 
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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 
 
Filgrastim 
 
SC 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.8 mL 
 
 
6. OTHER 
 
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B. PACKAGE LEAFLET 
 

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Package leaflet: Information for the user 
 

Biograstim 30 MIU/0.5 mL solution for injection or infusion 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 

 
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 Biograstim is and what it is used for 
2. What you need to know before you use Biograstim 
3. How to use Biograstim 
4. Possible side effects 
5. How to store Biograstim 
6. Contents of the pack and other information 
7. Information for injecting yourself 
8. The following information is intended for healthcare professionals only 
 
 
1. What Biograstim is and what it is used for 
 
What Biograstim is 
Biograstim contains the active substance filgrastim. Filgrastim is a protein produced by biotechnology 
in bacteria called Escherichia coli. It belongs to a group of proteins called cytokines and is very 
similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by your own 
body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to produce 
more blood cells, especially certain types of white cells. White cells are important as they help your 
body fight infection. 
 
What Biograstim is used for 
Your doctor has prescribed Biograstim for you to help your body make more white blood cells. Your 
doctor will tell you why you are being treated with Biograstim. Biograstim is useful in several 
different conditions, which are: 
- chemotherapy; 
- bone marrow transplantation; 
- severe chronic neutropenia (low white blood cell count); 
- neutropenia in patients with HIV infection; 
- peripheral blood stem cell mobilisation (for blood stem cell donation). 
 
 
2. What you need to know before you use Biograstim 
 
Do not use Biograstim 
- if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in 

section 6). 
 

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Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Biograstim 
- if you experience a cough, fever and difficulty breathing. It could be a consequence of a 

pulmonary disorder (see section “4. Possible side effects”). 
- if you have sickle cell disease (an inherited disease characterised by sickle-shaped red blood 

cells). 
- if you get left upper abdominal pain or pain at the tip of your shoulder. It could be a 

consequence of a spleen disorder (see section “4. Possible side effects”). 
- if you have specific blood disorders (e.g. Kostman's syndrome, myelodysplastic syndrome, 

different types of leukaemia).  
- if you have osteoporosis. Your doctor might check your bone density regularly.  
- if you are suffering from any other illness, especially if you think you have an infection. 
 
Talk to your doctor or nurse that you are treated with Biograstim if you are undergoing bone-imaging. 
 
You will need to have regular blood tests whilst being treated with Biograstim to count the number of 
neutrophils and other white blood cells in your blood. This will tell your doctor how well the 
treatment is working and will also indicate if treatment needs to be continued. 
 
Other medicines and Biograstim 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Do not use Biograstim in the 24 hours before or the 24 hours after your chemotherapy. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
Biograstim has not been tested in pregnant women. Therefore, your doctor may decide that you 
should not use this medicine. 
It is unknown whether filgrastim passes over to the breast milk. Therefore, your doctor may decide 
that you should not use this medicine if you are breast-feeding. 
 
Driving and using machines 
If you experience fatigue, do not drive or use any tools or machines. 
 
Biograstim contains sorbitol and sodium 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before using this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 
‘sodium-free’. 
 
 
3. How to use Biograstim 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is... 
The amount of Biograstim you need, will depend on the condition you are taking Biograstim for and 
on your bodyweight. Your doctor will tell you when to stop using Biograstim. It is quite normal to 
have a number of courses of Biograstim treatment. 
 
Biograstim and chemotherapy 
The usual dose is 0.5 million international units (MIU) per kilogram of bodyweight each day. For 
example, if you weigh 60 kg your daily dose will be 30 million international units (MIU). You will 

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normally receive your first dose of Biograstim at least 24 hours after your chemotherapy. Your 
treatment will usually last for about 14 days. In some disease types however, longer treatment lasting 
up to about one month may be required. 
 
Biograstim and bone marrow transplantation 
The usual starting dose is 1 million international units (MIU) per kilogram of bodyweight each day. 
For example, if you weigh 60 kg your daily dose will be 60 million international units (MIU). You 
will normally receive your first dose of Biograstim at least 24 hours after your chemotherapy but 
within 24 hours of receiving your bone marrow transfusion. Your doctor will test your blood daily to 
see how well the treatment is working and to find the dose that is best for you. The treatment will be 
discontinued when white cells in your blood reach a certain number. 
 
Biograstim and severe chronic neutropenia 
The usual starting dose is between 0.5 million and 1.2 million international units (MIU) per kilogram 
bodyweight each day in a single or divided dose. Your doctor will then test your blood to see how 
well your treatment is working and to find the dose that is best for you. Long-term treatment with 
Biograstim is required for neutropenia. 
 
Biograstim and neutropenia in patients with HIV infection 
The usual starting dose is between 0.1 and 0.4 million international units (MIU) per kilogram 
bodyweight each day. Your doctor will test your blood at regular intervals to see how well the 
treatment is working. Once the number of white cells in your blood have returned to normal it may be 
possible to reduce the dose frequency to less than once per day. Your doctor will continue to test your 
blood regularly and will recommend the best dose for you. Long-term treatment with Biograstim may 
be required to maintain a normal number of white cells in your blood. 
 
Biograstim and peripheral blood stem cell mobilisation 
If you are donating stem cells for yourself, the usual dose is 0.5 million to 1 million international units 
(MIU) per kilogram bodyweight each day. Biograstim treatment will last for up to 2 weeks and in 
exceptional cases longer. 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 international units 
(MIU) per kilogram bodyweight each day. Biograstim treatment will last for 4 to 5 days. 
 
Method of administration 
This medicine is given by injection, either through an intravenous (IV) infusion (drip) or a 
subcutaneous (SC) injection (into the tissue just under the skin). 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. Do not attempt to self-administer 
without this training. Some of the information you require is given at the end of this package leaflet, 
but proper treatment of your disease requires close and constant co-operation with your doctor. 
 
If you use more Biograstim than you should 
If you use more Biograstim than you should, contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Biograstim 
Do not use a double dose to make up for a forgotten injection. 
 
If you stop using Biograstim 
Before you stop using Biograstim, talk to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 

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Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Important side effects 
 
- Allergic reactions such as skin rash, raised itchy areas of skin and serious allergic reactions with 

weakness, drop in blood pressure, difficulty breathing and swelling of the face have been 
reported. If you think you are having this type of reaction, you must stop your Biograstim 
injection and get medical help immediately. 

 
- Increased spleen size and cases of spleen ruptures have been reported. Some cases of splenic 

rupture were fatal. It is important to contact your doctor immediately if you experience pain in 
the upper left side of the abdomen or left shoulder pain since this may relate to a problem with 
your spleen. 

 
- Cough, fever and difficult or painful breathing can be signs of serious pulmonary side effects, 

such as pneumonia and acute respiratory distress syndrome, which may be fatal. If you have a 
fever or any of these symptoms, it is important to contact your doctor immediately. 

 
- It is important to contact your doctor immediately 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 an uncommon (may affect up to 1 in 100 people) 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 Sickle Cell Disease, make sure that you tell your doctor before you start taking 

Biograstim. Sickle cell crisis has happened in some patients with Sickle Cell Disease who have 
been given filgrastim. 

 
- As a very common (may affect more than 1 in 10 people) side effect, filgrastim may cause bone 

and muscle pain. Ask your doctor which medicine you can take to help with this. 
 
You may experience the following additional side effects: 
 
In cancer patients 
 
Very common (may affect more than 1 in 10 people): 
- elevated levels of some liver or blood enzymes; high blood levels of uric acid; 
- feeling sick; vomiting; 
- chest pain. 
 
Common (may affect up to 1 in 10 people): 
- headache; 
- cough; sore throat; 
- constipation; loss of appetite; diarrhoea; mucositis, which is painful inflammation and 

ulceration of the mucous membranes lining the digestive tract; 
- hair loss; rash; 
- fatigue; generalised weakness. 
 
Uncommon (may affect up to 1 in 100 people): 
- unspecified pain. 
 
Rare (may affect up to 1 in 1,000 people): 

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- vascular disorders, which can cause pain, redness and swelling in the limbs. 
 
Very rare (may affect up to 1 in 10,000 people): 
- painful, raised, plum-coloured sores on the limbs and sometimes the face and neck with fever 

(Sweet's syndrome); inflammation of blood vessels, often with skin rash; 
- worsening of rheumatic conditions; 
- pains or difficulties in passing urine. 
 
Not known (frequency cannot be estimated from the available data): 
- rejection of transplanted bone marrow; 
- transient low blood pressure; 
- pain and swelling of the joints, similar to gout. 
 
In normal stem cell donors 
 
Very common (may affect more than 1 in 10 people): 
- rise in white blood cells; reduction in blood platelets, which increases risk of bleeding or 

bruising; 
- headache. 
 
Common (may affect up to 1 in 10 people): 
- elevated levels of some blood enzymes. 
 
Uncommon (may affect up to 1 in 100 people): 
- elevated levels of some liver enzymes; high blood levels of uric acid; 
- worsening of rheumatic conditions. 
 
Not known (frequency cannot be estimated from the available data): 
- cough; fever and difficulty breathing or coughing up blood. 
 
In severe chronic neutropenia patients 
 
Very common (may affect more than 1 in 10 people): 
- reduction in red blood cells, which can make the skin pale and cause weakness or 

breathlessness; 
- low blood levels of glucose; elevated levels of some blood enzymes; high blood levels of uric 

acid; 
- nosebleed. 
 
Common (may affect up to 1 in 10 people): 
- reduction in blood platelets, which increases risk of bleeding or bruising; 
- headache; 
- diarrhoea; 
- enlargement of the liver; 
- hair loss; inflammation of blood vessels, often with skin rash; pain at the site of injection; rash; 
- loss of calcium from the bones; joint pain. 
 
Uncommon (may affect up to 1 in 100 people): 
- blood in the urine; protein in the urine. 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. 
 
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 

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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 Biograstim 
 
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 that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
 
Do not use this medicine if you notice it is cloudy or there are particles in it. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Biograstim contains 
- The active substance is filgrastim. Each mL of solution for injection or infusion contains 

60 million international units [MIU] (600 microgram) of filgrastim. 
Biograstim 30 MIU/0.5 mL: Each pre-filled syringe contains 30 million international units 
[MIU] (300 microgram) of filgrastim in 0.5 mL solution. 
Biograstim 48 MIU/0.8 mL: Each pre-filled syringe contains 48 million international units 
[MIU] (480 microgram) of filgrastim in 0.8 mL solution. 

- The other ingredients are: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water 
for injections. 

 
What Biograstim looks like and contents of the pack 
Biograstim is a solution for injection or infusion in a pre-filled syringe with or without safety device. 
Biograstim is a clear and colourless solution. Each pre-filled syringe contains either 0.5 mL or 0.8 mL 
of solution. 
 
Biograstim is supplied in packs of 1, 5 or 10 pre-filled syringes or multipacks of 10 (2 packs of 5) 
pre-filled syringes. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
Manufacturer 
Merckle Biotec GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
This leaflet was last revised in . 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

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7. Information for injecting yourself 
 
This section contains information on how to give yourself an injection of Biograstim. It is important 
that you do not try to give yourself the injection unless you have received special training from your 
doctor or nurse. If you are not sure about giving yourself the injection or you have any questions, 
please ask your doctor or nurse for help. 
 
It is important that you dispose of used syringes in a puncture-proof container. 
 
How do I inject Biograstim myself? 
You will need to give yourself the injection into the tissue just under the skin. This is known as a 
subcutaneous injection. You will need to have your injections at about the same time every day. 
 
Equipment that you need 
To give yourself a subcutaneous injection you will need: 
- a pre-filled syringe of Biograstim; 
- alcohol wipes or similar; 
- a puncture-proof container (plastic container provided by the hospital or pharmacy) so you can 

dispose of used syringes safely. 
 
What should I do before I give myself a subcutaneous injection of Biograstim? 
1. Try to self-inject at approximately the same time every day. 
2. Take your Biograstim pre-filled syringe out of the refrigerator. 
3. Check the expiry date on the pre-filled syringe label (EXP). Do not use it if the date has passed 

the last day of the month shown. 
4. Check the appearance of Biograstim. It must be a clear and colourless liquid. If there are 

particles in it, you must not use it. 
5. For a more comfortable injection, let the pre-filled syringe stand for 30 minutes to reach room 

temperature or hold the pre-filled syringe gently in your hand for a few minutes. Do not warm 
Biograstim in any other way (for example, do not warm it in a microwave or in hot water). 

6. Do not remove the cover from the syringe until you are ready to inject. 
7. Wash your hands thoroughly. 
8. Find a comfortable, well-lit place and put everything you need where you can reach them (the 

Biograstim pre-filled syringe, alcohol wipes and the puncture-proof container). 
 
How do I prepare my Biograstim injection? 
Before you inject Biograstim you must do the following: 
1. Hold the syringe and gently take the cover from the needle without twisting. Pull straight as 

shown in pictures 1 and 2. Do not touch the needle or push the plunger. 
 

1 2 
 
2. You may notice a small air bubble in the pre-filled syringe. If there are air bubbles present, 

gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. With 
the syringe pointing upwards, expel all air from the syringe by pushing the plunger upwards. 

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3. The syringe has a scale on the syringe barrel. Push the plunger up to the number (mL) on the 
syringe that matches the dose of Biograstim that your doctor prescribed. 

4. Check again to make sure the correct dose of Biograstim is in the syringe. 
5. You can now use the pre-filled syringe. 
 
Where should I give my injection? 
The most suitable places to inject yourself are: 
- the top of your thighs; and 
- the abdomen, except for the area around the navel (see picture 3). 
 

3 4 
 
If someone else is injecting you, they can also use the back of your arms (see picture 4). 
 
It is better to change the injection site every day to avoid the risk of soreness at any one site. 
 
How do I give my injection? 
1. Disinfect the injection site by using an alcohol wipe and pinch the skin between your thumb 

and forefinger, without squeezing it (see picture 5). 
2. Put the needle fully into the skin as shown by your nurse or doctor (see picture 6). 
3. Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see 

blood in the syringe, remove the needle and re-insert it in another place. 
4. Inject the liquid slowly and evenly, always keeping your skin pinched. 
5. Inject only the dose your doctor has told you. 
6. After injecting the liquid, remove the needle and let go of your skin. 
7. Only use each syringe for one injection. Do not use any Biograstim that is left in the syringe. 
 

5 6 
 
Remember 
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice. 
 
Disposing of used syringes 
- Do not put the cover back on used needles. 
- Put used syringes into the puncture-proof container and keep this container out of the sight and 

reach of children. 

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- Dispose of the full puncture-proof container as instructed by your doctor, nurse or pharmacist. 
- Never put the syringes that you have used into your normal household rubbish bin. 
 
 
8. The following information is intended for healthcare professionals only 
 
Biograstim does not contain any preservative. In view of the possible risk of microbial contamination, 
Biograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Biograstim. 
 
Biograstim should not be diluted with sodium chloride solution. This medicinal product must not be 
mixed with other medicinal products except those mentioned below. Diluted filgrastim may be 
adsorbed to glass and plastic materials except diluted, as mentioned below. 
 
If required, Biograstim may be diluted in glucose 50 mg/mL (5 %) solution for infusion. Dilution to a 
final concentration less than 0.2 MIU (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 MIU (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 MIU (300 μg) should be given with 0.2 mL of 
200 mg/mL (20 %) human albumin solution added. When diluted in glucose 50 mg/mL (5 %) solution 
for infusion, Biograstim is compatible with glass and a variety of plastics including PVC, polyolefin 
(a co-polymer 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. 

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Package leaflet: Information for the user 
 

Biograstim 30 MIU/0.5 mL solution for injection or infusion 
Biograstim 48 MIU/0.8 mL solution for injection or infusion 

 
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 Biograstim is and what it is used for 
2. What you need to know before you use Biograstim 
3. How to use Biograstim 
4. Possible side effects 
5. How to store Biograstim 
6. Contents of the pack and other information 
7. Information for injecting yourself 
8. The following information is intended for healthcare professionals only 
 
 
1. What Biograstim is and what it is used for 
 
What Biograstim is 
Biograstim contains the active substance filgrastim. Filgrastim is a protein produced by biotechnology 
in bacteria called Escherichia coli. It belongs to a group of proteins called cytokines and is very 
similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by your own 
body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to produce 
more blood cells, especially certain types of white cells. White cells are important as they help your 
body fight infection. 
 
What Biograstim is used for 
Your doctor has prescribed Biograstim for you to help your body make more white blood cells. Your 
doctor will tell you why you are being treated with Biograstim. Biograstim is useful in several 
different conditions, which are: 
- chemotherapy; 
- bone marrow transplantation; 
- severe chronic neutropenia (low white blood cell count); 
- neutropenia in patients with HIV infection; 
- peripheral blood stem cell mobilisation (for blood stem cell donation). 
 
 
2. What you need to know before you use Biograstim 
 
Do not use Biograstim 
- if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in 

section 6). 
 

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Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Biograstim 
- if you experience a cough, fever and difficulty breathing. It could be a consequence of a 

pulmonary disorder (see section “4. Possible side effects”). 
- if you have sickle cell disease (an inherited disease characterised by sickle-shaped red blood 

cells). 
- if you get left upper abdominal pain or pain at the tip of your shoulder. It could be a 

consequence of a spleen disorder (see section “4. Possible side effects”). 
- if you have specific blood disorders (e.g. Kostman's syndrome, myelodysplastic syndrome, 

different types of leukaemia).  
- if you have osteoporosis. Your doctor might check your bone density regularly.  
- if you are suffering from any other illness, especially if you think you have an infection. 
 
Talk to your doctor or nurse that you are treated with Biograstim if you are undergoing bone-imaging. 
 
You will need to have regular blood tests whilst being treated with Biograstim to count the number of 
neutrophils and other white blood cells in your blood. This will tell your doctor how well the 
treatment is working and will also indicate if treatment needs to be continued. 
 
Other medicines and Biograstim 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Do not use Biograstim in the 24 hours before or the 24 hours after your chemotherapy. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
Biograstim has not been tested in pregnant women. Therefore, your doctor may decide that you 
should not use this medicine. 
It is unknown whether filgrastim passes over to the breast milk. Therefore, your doctor may decide 
that you should not use this medicine if you are breast-feeding. 
 
Driving and using machines 
If you experience fatigue, do not drive or use any tools or machines. 
 
Biograstim contains sorbitol and sodium 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before using this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 
‘sodium-free’. 
 
 
3. How to use Biograstim 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is... 
The amount of Biograstim you need, will depend on the condition you are taking Biograstim for and 
on your bodyweight. Your doctor will tell you when to stop using Biograstim. It is quite normal to 
have a number of courses of Biograstim treatment. 
 
Biograstim and chemotherapy 
The usual dose is 0.5 million international units (MIU) per kilogram of bodyweight each day. For 
example, if you weigh 60 kg your daily dose will be 30 million international units (MIU). You will 

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normally receive your first dose of Biograstim at least 24 hours after your chemotherapy. Your 
treatment will usually last for about 14 days. In some disease types however, longer treatment lasting 
up to about one month may be required. 
 
Biograstim and bone marrow transplantation 
The usual starting dose is 1 million international units (MIU) per kilogram of bodyweight each day. 
For example, if you weigh 60 kg your daily dose will be 60 million international units (MIU). You 
will normally receive your first dose of Biograstim at least 24 hours after your chemotherapy but 
within 24 hours of receiving your bone marrow transfusion. Your doctor will test your blood daily to 
see how well the treatment is working and to find the dose that is best for you. The treatment will be 
discontinued when white cells in your blood reach a certain number. 
 
Biograstim and severe chronic neutropenia 
The usual starting dose is between 0.5 million and 1.2 million international units (MIU) per kilogram 
bodyweight each day in a single or divided dose. Your doctor will then test your blood to see how 
well your treatment is working and to find the dose that is best for you. Long-term treatment with 
Biograstim is required for neutropenia. 
 
Biograstim and neutropenia in patients with HIV infection 
The usual starting dose is between 0.1 and 0.4 million international units (MIU) per kilogram 
bodyweight each day. Your doctor will test your blood at regular intervals to see how well the 
treatment is working. Once the number of white cells in your blood have returned to normal it may be 
possible to reduce the dose frequency to less than once per day. Your doctor will continue to test your 
blood regularly and will recommend the best dose for you. Long-term treatment with Biograstim may 
be required to maintain a normal number of white cells in your blood. 
 
Biograstim and peripheral blood stem cell mobilisation 
If you are donating stem cells for yourself, the usual dose is 0.5 million to 1 million international units 
(MIU) per kilogram bodyweight each day. Biograstim treatment will last for up to 2 weeks and in 
exceptional cases longer. 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 international units 
(MIU) per kilogram bodyweight each day. Biograstim treatment will last for 4 to 5 days. 
 
Method of administration 
This medicine is given by injection, either through an intravenous (IV) infusion (drip) or a 
subcutaneous (SC) injection (into the tissue just under the skin). 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. Do not attempt to self-administer 
without this training. Some of the information you require is given at the end of this package leaflet, 
but proper treatment of your disease requires close and constant co-operation with your doctor. 
 
If you use more Biograstim than you should 
If you use more Biograstim than you should, contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Biograstim 
Do not use a double dose to make up for a forgotten injection. 
 
If you stop using Biograstim 
Before you stop using Biograstim, talk to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 

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Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Important side effects 
 
- Allergic reactions such as skin rash, raised itchy areas of skin and serious allergic reactions with 

weakness, drop in blood pressure, difficulty breathing and swelling of the face have been 
reported. If you think you are having this type of reaction, you must stop your Biograstim 
injection and get medical help immediately. 

 
- Increased spleen size and cases of spleen ruptures have been reported. Some cases of splenic 

rupture were fatal. It is important to contact your doctor immediately if you experience pain in 
the upper left side of the abdomen or left shoulder pain since this may relate to a problem with 
your spleen. 

 
- Cough, fever and difficult or painful breathing can be signs of serious pulmonary side effects, 

such as pneumonia and acute respiratory distress syndrome, which may be fatal. If you have a 
fever or any of these symptoms, it is important to contact your doctor immediately. 

 
- It is important to contact your doctor immediately 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 an uncommon (may affect up to 1 in 100 people) 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 Sickle Cell Disease, make sure that you tell your doctor before you start taking 

Biograstim. Sickle cell crisis has happened in some patients with Sickle Cell Disease who have 
been given filgrastim. 

 
- As a very common (may affect more than 1 in 10 people) side effect, filgrastim may cause bone 

and muscle pain. Ask your doctor which medicine you can take to help with this. 
 
You may experience the following additional side effects: 
 
In cancer patients 
 
Very common (may affect more than 1 in 10 people): 
- elevated levels of some liver or blood enzymes; high blood levels of uric acid; 
- feeling sick; vomiting; 
- chest pain. 
 
Common (may affect up to 1 in 10 people): 
- headache; 
- cough; sore throat; 
- constipation; loss of appetite; diarrhoea; mucositis, which is painful inflammation and 

ulceration of the mucous membranes lining the digestive tract; 
- hair loss; rash; 
- fatigue; generalised weakness. 
 
Uncommon (may affect up to 1 in 100 people): 
- unspecified pain. 
 
Rare (may affect up to 1 in 1,000 people): 

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- vascular disorders, which can cause pain, redness and swelling in the limbs. 
 
Very rare (may affect up to 1 in 10,000 people): 
- painful, raised, plum-coloured sores on the limbs and sometimes the face and neck with fever 

(Sweet's syndrome); inflammation of blood vessels, often with skin rash; 
- worsening of rheumatic conditions; 
- pains or difficulties in passing urine. 
 
Not known (frequency cannot be estimated from the available data): 
- rejection of transplanted bone marrow; 
- transient low blood pressure; 
- pain and swelling of the joints, similar to gout. 
 
In normal stem cell donors 
 
Very common (may affect more than 1 in 10 people): 
- rise in white blood cells; reduction in blood platelets, which increases risk of bleeding or 

bruising; 
- headache. 
 
Common (may affect up to 1 in 10 people): 
- elevated levels of some blood enzymes. 
 
Uncommon (may affect up to 1 in 100 people): 
- elevated levels of some liver enzymes; high blood levels of uric acid; 
- worsening of rheumatic conditions. 
 
Not known (frequency cannot be estimated from the available data): 
- cough; fever and difficulty breathing or coughing up blood. 
 
In severe chronic neutropenia patients 
 
Very common (may affect more than 1 in 10 people): 
- reduction in red blood cells, which can make the skin pale and cause weakness or 

breathlessness; 
- low blood levels of glucose; elevated levels of some blood enzymes; high blood levels of uric 

acid; 
- nosebleed. 
 
Common (may affect up to 1 in 10 people): 
- reduction in blood platelets, which increases risk of bleeding or bruising; 
- headache; 
- diarrhoea; 
- enlargement of the liver; 
- hair loss; inflammation of blood vessels, often with skin rash; pain at the site of injection; rash; 
- loss of calcium from the bones; joint pain. 
 
Uncommon (may affect up to 1 in 100 people): 
- blood in the urine; protein in the urine. 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. 
 
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 

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71 

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 Biograstim 
 
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 that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
 
Do not use this medicine if you notice it is cloudy or there are particles in it. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Biograstim contains 
- The active substance is filgrastim. Each mL of solution for injection or infusion contains 

60 million international units [MIU] (600 microgram) of filgrastim. 
Biograstim 30 MIU/0.5 mL: Each pre-filled syringe contains 30 million international units 
[MIU] (300 microgram) of filgrastim in 0.5 mL solution. 
Biograstim 48 MIU/0.8 mL: Each pre-filled syringe contains 48 million international units 
[MIU] (480 microgram) of filgrastim in 0.8 mL solution. 

- The other ingredients are: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water 
for injections. 

 
What Biograstim looks like and contents of the pack 
Biograstim is a solution for injection or infusion in a pre-filled syringe with or without safety device. 
Biograstim is a clear and colourless solution. Each pre-filled syringe contains either 0.5 mL or 0.8 mL 
of solution. 
 
Biograstim is supplied in packs of 1, 5 or 10 pre-filled syringes or multipacks of 10 (2 packs of 5) 
pre-filled syringes. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
AbZ-Pharma GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
Manufacturer 
Merckle Biotec GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
This leaflet was last revised in . 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

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7. Information for injecting yourself 
 
This section contains information on how to give yourself an injection of Biograstim. It is important 
that you do not try to give yourself the injection unless you have received special training from your 
doctor or nurse. If you are not sure about giving yourself the injection or you have any questions, 
please ask your doctor or nurse for help. 
 
How do I inject Biograstim myself? 
You will need to give yourself the injection into the tissue just under the skin. This is known as a 
subcutaneous injection. You will need to have your injections at about the same time every day. 
 
Equipment that you need 
To give yourself a subcutaneous injection you will need: 
- a pre-filled syringe of Biograstim; 
- alcohol wipes or similar. 
 
What should I do before I give myself a subcutaneous injection of Biograstim? 
1. Try to self-inject at approximately the same time every day. 
2. Take your Biograstim pre-filled syringe out of the refrigerator. 
3. Check the expiry date on the pre-filled syringe label (EXP). Do not use it if the date has passed 

the last day of the month shown. 
4. Check the appearance of Biograstim. It must be a clear and colourless liquid. If there are 

particles in it, you must not use it. 
5. For a more comfortable injection, let the pre-filled syringe stand for 30 minutes to reach room 

temperature or hold the pre-filled syringe gently in your hand for a few minutes. Do not warm 
Biograstim in any other way (for example, do not warm it in a microwave or in hot water). 

6. Do not remove the cover from the syringe until you are ready to inject. 
7. Wash your hands thoroughly. 
8. Find a comfortable, well-lit place and put everything you need where you can reach them (the 

Biograstim pre-filled syringe and alcohol wipes). 
 
How do I prepare my Biograstim injection? 
Before you inject Biograstim you must do the following: 
1. Hold the syringe and gently take the cover from the needle without twisting. Pull straight as 

shown in pictures 1 and 2. Do not touch the needle or push the plunger. 
 

1 2 
 
2. You may notice a small air bubble in the pre-filled syringe. If there are air bubbles present, 

gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. With 
the syringe pointing upwards, expel all air from the syringe by pushing the plunger upwards. 

3. The syringe has a scale on the syringe barrel. Push the plunger up to the number (mL) on the 
syringe that matches the dose of Biograstim that your doctor prescribed. 

4. Check again to make sure the correct dose of Biograstim is in the syringe. 
5. You can now use the pre-filled syringe. 

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73 

 
Where should I give my injection? 
The most suitable places to inject yourself are: 
- the top of your thighs; and 
- the abdomen, except for the area around the navel (see picture 3). 
 

3 4 
 
If someone else is injecting you, they can also use the back of your arms (see picture 4). 
 
It is better to change the injection site every day to avoid the risk of soreness at any one site. 
 
How do I give my injection? 
1. Disinfect the injection site by using an alcohol wipe and pinch the skin between your thumb 

and forefinger, without squeezing it (see picture 5). 
2. Put the needle fully into the skin as shown by your nurse or doctor (see picture 6). 
3. Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see 

blood in the syringe, remove the needle and re-insert it in another place. 
4. Inject the liquid slowly and evenly, always keeping your skin pinched. 
5. Inject only the dose your doctor has told you. 
6. Remove the syringe from the injection site while keeping your finger on the plunger (see 

picture 7). Orient the needle away from you and others and activate the safety device by firmly 
pushing the plunger (see picture 8). You will hear a “click”, which confirms activation of the 
safety device. The needle will be covered by the protective sleeve so that you cannot prick 
yourself. 

 

5 6 
 

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7 8 
 
Remember 
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice. 
 
Disposing of used syringes 
- The safety device prevents needle stick injuries after use, so no special precautions for disposal 

are required. Dispose of syringes with safety device as instructed by your doctor, nurse or 
pharmacist. 

 
 
8. The following information is intended for healthcare professionals only 
 
Biograstim does not contain any preservative. In view of the possible risk of microbial contamination, 
Biograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Biograstim. 
 
Biograstim should not be diluted with sodium chloride solution. This medicinal product must not be 
mixed with other medicinal products except those mentioned below. Diluted filgrastim may be 
adsorbed to glass and plastic materials except diluted, as mentioned below. 
 
If required, Biograstim may be diluted in glucose 50 mg/mL (5 %) solution for infusion. Dilution to a 
final concentration less than 0.2 MIU (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 MIU (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 MIU (300 μg) should be given with 0.2 mL of 
200 mg/mL (20 %) human albumin solution added. When diluted in glucose 50 mg/mL (5 %) solution 
for infusion, Biograstim is compatible with glass and a variety of plastics including PVC, polyolefin 
(a co-polymer 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. 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER 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