Ratiograstim

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 30 MIU/0.5 mL solution for injection/ infusion 
Ratiograstim 48 MIU/0.8 mL solution for injection/infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of solution for injection/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/infusion. 
Each pre-filled syringe contains 48 MIU (480 µg) of filgrastim in 0.8 mL solution for 
injection/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/infusion 
 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ratiograstim 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. 
 
Ratiograstim 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 Ratiograstim is indicated to increase neutrophil counts and to reduce the 
incidence and duration of infection-related events. 
 
Ratiograstim 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 
 



3 

 
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 
 
Posology 
 
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should be 
administered at least 24 hours after cytotoxic chemotherapy.  
In randomised clinical trials, a subcutaneous dose of 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. 
 
Method of administration 
 
Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 
5% glucose solution for infusion given over 30 minutes (see section 6.6). The subcutaneous route is 
preferred in most cases. There is some evidence from a study of single dose administration that 
intravenous dosing may shorten the duration of effect. The clinical relevance of this finding to 
multiple dose administration is not clear. The choice of route should depend on the individual clinical 
circumstance. 
 
In patients treated with myeloablative therapy followed by bone marrow transplantation 
 
Posology 
 
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day.  
The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and 
at least 24 hours after bone marrow infusion. 
 
Once the neutrophil nadir has been passed the daily dose of 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 
ANC = absolute neutrophil count 
 



4 

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



5 

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. 
 
Method of administration 
 
Congenital, idiopathic or cyclic neutropenia: 
 
Filgrastim should be given by subcutaneous injection. 
 
In patients with HIV infection 
 
Posology 
 
For reversal of neutropenia 
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day 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. 
 
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 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. 
 
Method of administration 
Reversal of neutropenia or maintaining normal neutrophil counts: 
Filgrastim should be given by subcutaneous injection. 
 
Special populations 
 
Elderly  
Clinical trials with filgrastim have included a small number of elderly patients but special studies have 
not been performed in this group and therefore specific dosage recommendations cannot be made. 
 
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 SCN. 
 



6 

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 warning and precautions across indications 
 
 
Hypersensitivity 
 
Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have 
been reported in patients treated with filgrastim. Permanently discontinue Ratiograstim in patients 
with clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of 
hypersensitivity to filgrastim or pegfilgrastim 
 
Pulmonary adverse effects 
Pulmonary adverse reactions, in particular interstitial lung disease, have been reported after G-CSF 
administration. Patients with a recent history of lung infiltrates or pneumonia may be at higher risk. 
The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs 
of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute 
respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment 
given. 
 
Glomerulonephritis 
Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, 
events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and 
pegfilgrastim. Urinalysis monitoring is recommended. 
 
Capillary leak syndrome 
 
Capillary leak syndrome which can be life threatening if treatment is delayed, has been reported after 
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). 
 
Splenomegaly and Splenic rupture 
 
Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported in 
patients and normal donors following administration of filgrastim. Some cases of splenic rupture were 
fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A 
diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper 
abdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop the 
progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a 
splenectomy was required. 
 
Malignant cell growth 
 
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects 
may also be seen on some non-myeloid cells in vitro. 



7 

 
Myelodysplastic syndrome or Chronic myeloid leukemia 
 
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or 
chronic myelogenous leukaemia have not been established. Filgrastim is not indicated for use in these 
conditions. Particular care should be taken to distinguish the diagnosis of blast transformation of 
chronic myeloid leukaemia from acute myeloid leukaemia. 
 
Acute myeloid leukaemia 
 
In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be 
administered with caution. The safety and efficacy of filgrastim administration in de novo AML 
patients aged < 55 years with good cytogenetics (t(8;21), t(15;17), and inv(16)) have not been 
established. 
 
Thrombocytopenia 
 
Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be 
monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be 
given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic 
neutropenia who develop thrombocytopenia (platelet count < 100 x 109/l). 
 
Leukocytosis 
 
White blood cell counts of 100 x 109/L or greater have been observed in less than 5 % of cancer 
patients receiving filgrastim at doses above 0.3 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. 
 
Immunogenicity 
 
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of 
antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all 
biologics; however, they have not been associated with neutralising activity at present. 
Aortitis 
 
Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The 
symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory 
markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by 
CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8. 
 
Special warning and precautions associated with co-morbidities 
 
Special precautions in sickle cell trait and sickle cell disease 
 
Sickle cell crisis, in some cases fatal, have been reported with the use of filgrastim in patients with 
sickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim in 
patients with sickle cell trait or sickle cell disease. 
 
Osteoporosis 
 
Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases 
who undergo continuous therapy with filgrastim for more than 6 months. 



8 

 
Special precautions in cancer patients 
 
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established 
dosage regimens. 
 
Risks associated with increased doses of chemotherapy 
 
Special caution should be used when treating patients with high dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic 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). 
 
Effect of chemotherapy on erythrocytes and thrombocytes 
 
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to 
myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy 
(e.g., full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and 
anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should 
be taken when administering single or combination chemotherapeutic agents which are known to 
cause severe thrombocytopenia. 
 
The use of filgrastim mobilised PBPCs has been shown to reduce the depth and duration of 
thrombocytopenia following myelosuppressive or myeloablative chemotherapy. 
 
 
Other special precautions 
 
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been 
studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil 
counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such 
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 
by tumour). 
 
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 
reported occasionally in patients undergoing high dose chemotherapy followed by transplantation. 
 
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF 
after allogeneic bone marrow transplantation (see section 4.8 and  5.1). 
 
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been 
associated with transient abnormal bone scans This should be considered when interpreting 
bone-imaging results. 
 
Special precautions in patients undergoing PBPC mobilisation 
 
Mobilisation 
 
There are no prospectively randomised comparisons of the two recommended mobilisation methods 
(filgrastim alone or in combination with myelosuppressive chemotherapy) within the same patient 
population. The degree of variation between individual patients and between laboratory assays of 
CD34+ cells mean that direct comparison between different studies is difficult. It is therefore difficult 
to recommend an optimum method. The choice of mobilisation method should be considered in 
relation to the overall objectives of treatment for an individual patient. 
 
Prior exposure to cytotoxic agents 
 



9 

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



10 

clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and 
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 
 
Special precautions in recipients of allogeneic PBPCs mobilised with filgrastim 
 
Current data indicate that immunological interactions between the allogeneic PBPC graft and the 
recipient may be associated with an increased risk of acute and chronic GvHD when compared with 
bone marrow transplantation. 
 
Special precautions in SCN patients 
 
Filgrastim should not be administered to patients with severe congenital neutropenia who develop 
leukaemia or have evidence of leukaemic evolution. 
 
Blood cell counts 
 
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 
which require close monitoring of cell counts 
 
Transformation to leukaemia or myelodysplastic syndrome 
 
Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic 
disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell 
counts with differential and platelet counts and an evaluation of bone marrow morphology and 
karyotype should be performed prior to treatment. 
 
There was a low frequency (approximately 3 %) of myelodysplastic syndromes (MDS) or leukaemia 
in clinical trial patients with SCN treated with filgrastim. This observation has only been made in 
patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease 
and are of uncertain relation to filgrastim therapy. A subset of approximately 12 % of patients who had 
normal cytogenetic evaluations at baseline was subsequently found to have abnormalities, including 
monosomy 7, on routine repeat evaluation. It is currently unclear whether long-term treatment of 
patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic 
transformation. It is recommended to perform morphologic and cytogenetic bone marrow 
examinations in patients at regular intervals (approximately every 12 months). 
 
Other special precautions 
 
Causes of transient neutropenia such as viral infections should be excluded. 
 
Haematuria was common andproteinuria occurred in a small number of patients. Regular urinalysis 
should be performed to monitor these events. 
 
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 
established. 
 
Special precautions in patients with HIV infection 
 
Blood cell counts 
 
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 



11 

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). 
 
Infections and malignancies causing myelosuppression 
 
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium 
avium complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating 
infections or malignancy, consider appropriate therapy for treatment of the underlying condition in 
addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on 
neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established. 
 
 
 
. 
 
All patients 
 
Sorbitol 
Ratiograstim contains sorbitol (E420). The additive effect of concomitantly given products containing 
sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. 
 
Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless 
strictly necessary. Infants and young children (below 2 years of age) may not yet be diagnosed with 
HFI. Medicinal products (containing sorbitol/fructose) given intravenously may be life-threatening 
and should not be given in this population unless there is an overwhelming clinical need and no 
alternatives are available. 
 
A detailed history of HFI symptoms has to be taken of each patient before giving this medicinal 
product. 
 
Sodium 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. 
essentially ‘sodium-free’. 
 
Traceability 
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade 
name of the administered product should be clearly recorded in the patient file. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxic 
chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing 
myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended 
in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small 
number of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severity 
of neutropenia may be exacerbated. 
 



12 

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 or limited amount of data from the use of filgrastim in pregnant women.  
Studies in animals have shown reproductive toxicity. An increased incidence of embryo-loss has been 
observed in rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity 
(see section 5.3). There are reports in the literature where the transplacental passage of filgrastim in 
pregnant women has been demonstrated. 
 
Filgrastim is not recommended during pregnancy..Breast-feeding 
It is unknown whether filgrastim/metabolites are  excreted in human breast milk. A risk to the 
breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue 
breast-feeding or to discontinue/abstain from filgrastim therapy taking into account the benefit of 
breast-feeding for the child and the benefit of therapy for the woman. 
 
Fertility 
Filgrastim did not affect reproductive performance or fertility in male or female rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Filgrastim may have a minor influence on the ability to drive and use machines.  Dizziness may occur 
following the administration of filgrastim (see section 4.8). 
 
4.8 Undesirable effects 
 
a. Summary of the safety profile 
 
The most serious adverse reactions that may occur during filgrastim treatment include: anaphylactic 
reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary 
leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or 
leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral 
blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.  
 
The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes 
bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal 
chest pain, neck pain), anaemia, vomiting, and nausea. In clinical trials in cancer patients 
musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients. 
 
b.Tabulated summary of adverse reactions 
 
The data in the tables below describe adverse reactions reported from clinical trials and spontaneous 
reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness.  
 



13 

MedDRA 
system 
organ class 

Very 
common 
(≥ 1/10) 

Common 
(≥ 1/100 to 
< 1/10) 

Uncommon 
(≥ 1/1,000 
to < 1/100) 

Rare 
(≥ 1/10,000 
to 
< 1/1,000) 

Very rare 
(< 1/10,000) 

Infections 
and 
Infestations 

 Sepsis 
Bronchitis 
Upper 
respiratory 
tract 
infection 
Urinary 
tract 
infection 

   

Blood and 
lymphatic 
system 
disorders 

Thrombocyt
openia 
Anaemiae 

Splenomega
lya 
Haemoglobi
n 
decreasede 

Leukocytosi
sa 

Splenic 
rupturea 
Sickle cell 
anaemia 
with crisisa 

 

Immune 
system 
disorders 

  Hypersensit
ivity 
Drug 
hypersensiti
vitya 
Graft versus 
Host 
Diseaseb 

Anaphylacti
c 
reaction 

 

Metabolis
m and 
nutrition 
disorders 

 Decreased 
appetitee  
Blood 
lactate 
dehydrogen
ase 
increased 

Hyperuricae
mia 
Blood uric 
acid 
increased 

Blood 
glucose 
decreased 
Pseudogouta 
(Chondrocal
cinosis 
Pyrophosph
ate) 
Fluid 
volume 
disturbances 

 

Psychiatic 
diorders 

 Insomnia    

Nervous 
system 
disorders 

Headachea Dizziness 
Hypoaesthe
sia 
Paraesthesia 

   

Vascular 
disorders 

 Hypertensio
n 
Hypotensio
n 

Veno-
occlusive 
diseased 
 
 

Capillary 
leak 
syndromea 
Aortitis 

 

Respirator
y, thoracic 
and 
mediastinal 
disorders 

 Haemoptysi
s 
Dyspnoea 
Cougha 
Oropharyng
eal 
paina,e 
Epistaxis 

Acute 
respiratory 
distress 
syndromea 
Respiratory 
failurea 
Pulmonary 
oedemaa 

  



14 

Pulmonary 
haemorrhag
e 
Interstitial 
lung 
diseasea 
Lung 
infiltrationa 
Hypoxia 

Gastro-
intestinal 
disorders 

Diarrhoeaa, e 
Vomitinga,e 
Nauseaa 

Oral pain 
Constipatio
ne 

   

Hepato-
biliary 
disorders 

 Hepatomeg
aly 
Blood 
alkaline 
phosphatase 
increased 

Aspartate 
aminotransf
erase 
increased 
Gamma-
glutamyl 
transferase 
increased 

  

Skin and 
sub-
cutaneous 
tissue 
disorders 

Alopeciaa Rasha 
Erythema 

Rash 
maculopapu
lar 

Cutaneous 
vasculitisa 
Sweets 
syndrome 
(acute 
febrile 
neutrophilic 
dermatosis) 

 

Musculo-
skeletal 
and 
connective 
tissue 
disorders 

Musculo-
skeletal 
painc 

Muscle 
spasms 

Osteoporosi
s 

Bone 
density 
decreased 
Exacerbatio
n of 
rheumatoid 
arthritis 

 

Renal and 
urinary 
disorders 

 Dysuria 
Haematuria 

Proteinuria Glomerulon
ephritis 
Urine 
abnormality 

 

General 
disorders 
and ad-
ministratio
n site 
conditions 

Fatiguea 
Mucosal  
inflammatio
na  
Pyrexia 

Chest paina 
Paina 
Astheniaa 
Malaisee 
Oedema 
peripherale 

Injection 
site 
reaction 

  

Injury, 
poisoning 
and 
procedural 
complicatio
ns 

 Transfusion 
reactione 

   

a See section c (Description of selected adverse reactions) 
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow 
transplantation (see section c) 
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, 
musculoskeletal chest pain, neck 
pain 



15 

d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or 
PBPC mobilization 
e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with 
the sequelae of the underlying malignancy or cytotoxic chemotherapy 
 
c. Description of selected adverse reactions 
 
Hypersensitivity 
 
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and 
hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in 
post marketing experience. Overall, reports were more common after IV administration. In some 
cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should 
be permanently discontinued in patients who experience a serious allergic reaction.  
 
Pulmonary adverse events 
 
In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung 
disease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome of 
respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see section 
4.4). 
 
Splenomegaly and Splenic rupture 
 
Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. 
Some cases of splenic rupture were fatal (see section 4.4). 
 
Capillary leak syndrome 
 
Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor use. 
These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple 
chemotherapy medications or undergoing apheresis (see section 4.4). 
 
Cutaneous vasculitis 
 
Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of 
vasculitis in patients receiving filgrastim is unknown. During long term use cutaneous vasculitis has 
been reported in 2% of SCN patients. 
 
Leukocytosis 
 
Leukocytosis (WBC > 50 x 109/l) was observed in 41% of normal donors and transient 
thrombocytopenia (platelets < 100 x 109/l) following filgrastim and leukapheresis was observed in 
35% of donors (see section 4.4). 
 
Sweets syndrome 
 
Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients 
treated with filgrastim. 
 
Pseudogout (chondrocalcinosis pyrophosphate) 
 
Pseudogout (chondrocalcinosis pyrophosphate) has been reported in patients with cancer treated with 
filgrastim. 
 
GvHD 
 



16 

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see section 4.4 and 5.1). 
 
d. Paediatric population 
 
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 
similar in both adults and children receiving cytotoxic chemotherapy suggesting no age-related 
differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was 
musculoskeletal pain‚ which is no different from the experience in the adult population. 
 
There is insufficient data to further evaluate filgrastim use in paediatric subjects. 
 
e. Other special populations 
 
Geriatric Use 
 
No overall differences in safety or effectiveness were observed between subjects over 65 years of age 
compared to younger adult (>18 years of age) subjects receiving cytotoxic chemotherapy and clinical 
experience has not identified differences in the responses between elderly and younger adult patients. 
 
There is insufficient data to evaluate filgrastim use in geriatric subjects for other approved filgrastim 
indications. 
 
Paediatric SCN patients 
 
Cases of decreased bone density and osteoporosis have been reported in paediatric patients with SCN 
receiving chronic treatment with filgrastim.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The effects of filgrastim overdosage have not been established.  
Discontinuation of filgrastim therapy usually results in a 50 % decrease in circulating neutrophils 
within 1 to 2 days, with a return to normal levels in 1 to 7 days. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC code: L03AA02 
 
Ratiograstim 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. Ratiograstim 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 



17 

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. 
 
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. 
 



18 

Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled 
dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with 
HIV infection treated with filgrastim show an increase in HIV replication. 
 
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on 
human endothelial cells. 
 
The efficacy and safety of Ratiograstim has been assessed in randomised, controlled phase III studies 
in breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences 
between Ratiograstim 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 Ratiograstim 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 Ratiograstim and the reference product was 
comparable after single and repeated subcutaneous administration. 
 
5.3 Preclinical safety data 
 
Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed 
changes attributable to the expected pharmacological actions including increases in leukocytes, 
myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These 
changes all reversed after discontinuation of treatment. 
 
Effects of filgrastim on pre-natal development have been studied in rats and rabbits. Intravenous 
(80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was 
maternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live 
litter size and foetal weight were observed. 
 
Based on reported data for another filgrastim product similar to the reference product, comparable 
findings plus increased foetal malformations were observed at 100 µg/kg/day, a maternally toxic dose 
which corresponded to a systemic exposure of approximately 50-90 times the exposures observed in 
patients treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level for 
embryo-foetal toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of 
approximately 3-5 times the exposures observed in patients treated with the clinical dose. 
 
In pregnant rats, no maternal or foetal toxicity was observed at doses up to 575 µg/kg/day. Offspring 
of rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external 
differentiation and growth retardation (≥ 20 µg/kg/day) and slightly reduced survival rate 
(100 µg/kg/day). 
 
Filgrastim had no observed effect on the fertility of male or female rats. 
 



19 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Acetic acid, glacial 
Sodium hydroxide 
Sorbitol (E420) 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Ratiograstim 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. 
 
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. 
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, Ratiograstim 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. 



20 

 
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, Ratiograstim is compatible with glass 
and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) 
and polypropylene. 
 
Ratiograstim does not contain any preservative. In view of the possible risk of microbial 
contamination, Ratiograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/001 
EU/1/08/444/002 
EU/1/08/444/003 
EU/1/08/444/004 
EU/1/08/444/009 
EU/1/08/444/010 
EU/1/08/444/005 
EU/1/08/444/006 
EU/1/08/444/007 
EU/1/08/444/008 
EU/1/08/444/011 
EU/1/08/444/012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 September 2008. 
Date of latest renewal: 19 July 2013. 
 
 
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/. 
  



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



22 

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

 
Name and address of the manufacturer of the biological active substance 
 
UAB Teva Baltics 
Molėtų pl. 5  
08409 Vilnius 
Lithuania 
 
Name and address of the manufacturer responsible for batch release 
 
Teva Biotech GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
Merckle GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch 
 
 
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. 



23 

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

  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 30 MIU/0.5 mL solution for injection/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/infusion 
 
1 pre-filled syringe containing 0.5 mL 
1 pre-filled syringe with safety device 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 
 



27 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/001 1 pre-filled syringe 
EU/1/08/444/002 5 pre-filled syringes 
EU/1/08/444/004 10 pre-filled syringes 
EU/1/08/444/009 1 pre-filled syringe with safety device 
EU/1/08/444/010 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 
 
Ratiograstim 30 MIU/0.5 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 



28 

2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 48 MIU/0.8 mL solution for injection/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/infusion 
 
1 pre-filled syringe containing 0.8 mL 
1 pre-filled syringe with safety device 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 
 



30 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/005 1 pre-filled syringe 
EU/1/08/444/006 5 pre-filled syringes 
EU/1/08/444/008 10 pre-filled syringes 
EU/1/08/444/011 1 pre-filled syringe with safety device 
EU/1/08/444/012 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 
 
Ratiograstim 48 MIU/0.8 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 



31 

2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Wrapper Label on Multipacks- With Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 30 MIU/0.5 mL solution for injection/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/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 
 
EXP 



33 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/003 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 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Wrapper Label on Multipacks - With Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 48 MIU/0.8 mL solution for injection/ 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/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 
 
EXP 



35 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/007 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 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



36 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
Multipack Carton - Without Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 30 MIU/0.5 mL solution for injection/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/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 
 
EXP 



37 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/003 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 
 
Ratiograstim 30 MIU/0.5 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
  



38 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
Multipack Carton - Without Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ratiograstim 48 MIU/0.8 mL solution for injection/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/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 
 
EXP 



39 

 
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 
 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/444/007 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 
 
Ratiograstim 48 MIU/0.8 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
  



40 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ratiograstim 30 MIU/0.5 mL solution for injection/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 
 
 
  



41 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ratiograstim 48 MIU/0.8 mL solution for injection/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 
 
 

  



42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



43 

Package leaflet: Information for the user 
 

Ratiograstim 30 MIU/0.5 mL solution for injection/infusion 
Ratiograstim 48 MIU/0.8 mL solution for injection/ 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 Ratiograstim is and what it is used for 
2. What you need to know before you use Ratiograstim 
3. How to use Ratiograstim 
4. Possible side effects 
5. How to store Ratiograstim 
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 Ratiograstim is and what it is used for 
 
What Ratiograstim is 
Ratiograstim is a white blood cell growth factor (granulocyte colony stimulating factor) and belong to 
a group of medicines called cytokines. Growth factors are proteins that are produced naturally in the 
body but they can also be made using biotechnology for use as a medicine. Ratiograstim works by 
encouraging the bone marrow to produce more white blood cells. 
What Ratiograstim is used for 
A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes 
your body less able to fight infection. Ratiograstim stimulates the bone marrow to produce new white 
cells quickly. 
 
Ratiograstim can be used 
- to increase the number of white blood cells after treatment with chemotherapy to help prevent 

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

infections. 
- before high-dose chemotherapy to make the bone marrow produce more stem cells which can be 

collected and given back to you after your treatment. These can be taken from you or from a 
donor. The stem cells will then go back into the bone marrow and produce blood cells. 

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

- in patients with advanced HIV infection which will help reduce the risk of infections. 
 
2. What you need to know before you use Ratiograstim 
 
Do not use Ratiograstim 



44 

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

 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Ratiograstim. 
 
Please tell your doctor before starting treatment, if you have 
 
-  
- sickle cell anaemia, as this medicine may cause sickle cell crisis - osteoporosis (bone 

disease).  
 
Talk to your doctor immediately during treatment with Ratiograstim, if you: 

- have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, 
lips,tongue or other parts of the body, shortness of breath, wheezing or trouble breathing as 
these could be signs of a severe allergic reaction (hypersensitivity). 

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

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

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

- Inflammation of aorta (the large blood vessel which transports blood from the heart to the 
body) has been reported rarely in cancer patients and healthy donors. The symptoms can 
include fever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell 
your doctor if you experience those symptoms. 

 
Loss of response to filgrastim 
 
If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 
doctor will investigate the reasons why including whether you have developed antibodies which 
neutralise filgrastim’s activity. 
 
. 
 
Your doctor may want to monitor you closely, see section 4 of the package leaflet (If you are a patient 
with severe chronic neutropenia, you may be at risk of developing cancer of the blood (leukaemia, 
myelodysplastic syndrome [MDS]). You should talk to your doctor about your risks of developing 
cancers of the blood and what testing should be done. If you develop or are likely to develop cancers 
of the blood, you should not use Ratiograstim, unless instructed by your doctor. 
 
If you are a stem cell donor, you must be aged between 16 and 60 years. 
 
Take special care with other products that stimulate white blood cells 
 
Ratiograstim is one of a group of products that stimulate the production of white blood cells. Your 
healthcare professional should always record the exact product you are using. 
 
Other medicines and Ratiograstim 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
 
Pregnancy and breast-feeding 
Ratiograstim has not been tested in pregnant or breast-feeding women.  
 
Ratiograstim is not recommended during pregnancy. 



45 

 
It is important to tell your doctor if you: 
 

• are pregnant or breast-feeding 
• think you may be pregnant or  
• are planning to have a baby 

If you become pregnant during Ratiograstim treatment, please inform your doctor.. Unless your doctor 
directs you otherwise, you must stop breast-feeding if you use Ratiograstim  
 
Driving and using machines 
Ratiograstim may have a minor influence on your ability to drive and use machines. This medicine 
may cause dizziness. It is advisable to wait and see how you feel after using this medicine and before 
driving or operating machinery.  
 
Ratiograstim contains sorbitol 
This medicine contains 50 mg sorbitol in each mL. 
 
Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare 
genetic disorder, you (or your child) must not receive this medicine. Patients with HFI cannot break 
down fructose, which may cause serious side effects. You must tell your doctor before receiving this 
medicine if you (or your child) have HFI or if your child can no longer take sweet foods or drinks 
because they feel sick, vomit or get unpleasant effects such as bloating, stomach cramps or diarrhoea 
Ratiograstim contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 
‘sodium-free’. 
 
 
3. How to use Ratiograstim 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
How is Ratiograstim given and much should I take? 
 
Ratiograstim is usually given as a daily injection into the tissue just under the skin (known as a 
subcutaneous injection). It can also be given as a daily slow injection into the vein (known as an 
intravenous infusion). The usual dose varies depending on your illness and weight. Your doctor will 
tell you how much Ratiograstim you should take. 
 
Patients having a bone marrow transplant after chemotherapy: 
You will normally receive your first dose of Ratiogratsim at least 24 hours after your chemotherapy 
and at least 24 hours after receiving your bone marrow transplant. 
 
You, or people caring for you, can be taught how to give subcutaneous injections so that you can 
continue your treatment at home. However, you should not attempt this unless you have been properly 
trained first by your health care provider. 
 
How long will I have to take Ratiograstim? 
You will need to take Ratiograstim until your white blood cell count is normal. Regular blood tests 
will be taken to monitor the number of white blood cells in your body. Your doctor will tell you how 
long you will need to take Ratiograstim. 
 
 
 
 
Use in children 



46 

Ratiograstim is used to treat children who are receiving chemotherapy or who suffer from severe low 
white blood cell count (neutropenia). The dosing in children receiving chemotherapy is the same as for 
adults. 
 
 
If you use more Ratiograstim than you should 
Do not increase the dose your doctor has given you. If you use more Ratiograstim than you should, 
contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Ratiograstim 
If you have missed an injection, or injected too little, contact your doctor as soon as possible. Do not 
take a double dose to make up for any missed doses. 
 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Important side effects 
 
It is important to contact your doctor immediately 
- if you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face lips, 
mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea). 
- if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of 

Acute Respiratory Distress Syndrome (ARDS). 
- if you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients 

who received filgrastim. Call your doctor right away if you experience puffiness in your face or 
ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual. 

 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 condition called “capillary leak syndrome”, which causes blood to 
leak from the small blood vessels into your body and needs urgent medical attention. 

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

- fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, shortness 
of breath, extreme pain or discomfort and clammy or sweaty skin. 

These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 
severe infection with whole-body inflammatory response which can be life threatening and 
needs urgent medical attention. 

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

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

A common side effect of Ratiograstim use is pain in your muscles or bones (musculoskeletal pain), 
which could be relieved by taking standard pain relief medicines (analgesics). In patients undergoing a 
stem cell or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of 
the donor cells against the patient receiving the transplant; signs and symptoms include rash on the 
palms of your hands or soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your 
eyes, lungs, vagina and joints. 



47 

 
In normal stem cell donors an increase in white blood cells (leukocytosis) and a decrease of platelets 
may be seen this reduces the ability of your blood to clot (thrombocytopenia), these will be monitored 
by your doctor. 
 
 
You may experience the following side effects: 
 
 
Very common (may affect more than 1 in 10 people): 

• decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 
• low red blood cell count (anaemia) 
• headache 
• diarrhoea 
• vomiting 
• nausea 
• unusual hair loss or thinning (alopecia) 
• tiredness (fatigue) 
• soreness and swelling of the digestive tract lining which runs from the mouth to the anus 

(mucosal inflammation) 
• fever (pyrexia) 

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

• inflammation of the lung (bronchitis) 
• upper respiratory tract infection 
• urinary tract infection 
• decreased appetite 
• trouble sleeping (insomnia) 
• dizziness 
• decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 
• tingling or numbness of the hands or feet (paraesthesia) 
• low blood pressure (hypotension) 
• high blood pressure (hypertension) 
• cough 
• coughing up blood (haemoptysis) 
• pain in your mouth and throat (oropharyngeal pain) 
• nose bleeds (epistaxis) 
• constipation 
• oral pain 
• enlargement of the liver (hepatomegaly) 
• rash 
• redness of the skin (erythema) 
• muscle spasm 
• pain when passing urine (dysuria) 
• chest pain 
• pain 
• generalised weakness (asthenia) 
• generally feeling unwell (malaise) 
• swelling in the hands and feet (oedema peripheral) 
• increase of certain enzymes in the blood 
• changes in blood chemistry 
• transfusion reaction 

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

• increase in white blood cells (leukocytosis) 



48 

• allergic reaction (hypersensitivity) 
• rejection of transplanted bone marrow (graft versus host disease) 
• high uric acid levels in the blood, which may cause gout (hyperuricaemia) (blood uric acid 

increased) 
• liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 
• lungs do not function as they should, causing breathlessness (respiratory failure) 
• swelling and/or fluid in the lungs (pulmonary oedema) 
• inflammation of the lungs (interstitial lung disease) 
• abnormal x-rays of the lungs (lung infiltration) 
• bleeding from the lung (pulmonary haemorrhage) 
• lack of absorption of oxygen in the lung (hypoxia) 
• bumpy skin rash (rash macuo-papular) 
• disease which causes bones to become less dense, making them weaker, more brittle and 

likely to break (osteoporosis) 
• injection site reaction 

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

• severe pain in the bones, chest, gut or joints (sickle cell anaemia with crisis) 
• sudden life-threatening allergic reaction (anaphylactic reaction 
• pain and swelling of the joints, similar to gout (pseudogout) 
• a change in how your body regulates fluids within your body and may result in puffiness (fluid 

volume disturbances) 
• inflammation of the blood vessels in the skin (cutaneous vasculitis) 
• plum-coloured, raised, painful sores on the limbs and sometimes the face and neck with a 

fever (Sweets syndrome) 
• worsening of rheumatoid arthritis 
• unusual change in the urine 
• bone density decreased 
• Inflammation of aorta (the large blood vessel which transports blood from the heart to the 

body), see section 2 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Ratiograstim 
 
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 



49 

 
What Ratiograstim contains 
- The active substance is filgrastim. Each mL of solution for injection/infusion contains 

60 million international units [MIU] (600 microgram) of filgrastim. 
Ratiograstim 30 MIU/0.5 mL: Each pre-filled syringe contains 30 million international units 
[MIU] (300 microgram) of filgrastim in 0.5 mL solution. 
Ratiograstim 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 Ratiograstim looks like and contents of the pack 
Ratiograstim is a solution for injection/infusion in a pre-filled syringe with or without safety device. 
Ratiograstim is a clear and colourless solution. Each pre-filled syringe contains either 0.5 mL or 
0.8 mL of solution. 
 
Ratiograstim 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 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
Manufacturer 
Teva Biotech GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
Merckle GmbH 
Graf-Arco-Strasse 3 
89079 Ulm 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A./AG 
Tél/Tel: +32 3 820 73 73 
 

Lietuva 
UAB Teva Baltics 
Tel: +370 5 266 0203 
 

България 
Актавис ЕАД 
Teл: +359 2 489 95 85 
 

Luxembourg/Luxemburg 
ratiopharm GmbH 
Allemagne/Deutschland 
Tél/Tel: +49 731 402 02 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel.: +36 1 288 64 00 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Teva Pharmaceuticals Ireland 
L-Irlanda 
Tel: +353 19630330 
 



50 

Deutschland 
ratiopharm GmbH 
Tel: +49 731 402 02 
 

Nederland 
Teva Nederland B.V. 
Tel: +31 800 0228 400 
 

Eesti 
UAB Teva Baltics Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 211 880 5000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1 97 007 
 

España 
Teva Pharma, S.L.U. 
Tél: +34 91 387 32 80 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 22 345 93 00 
 

France 
Teva Santé 
Tél: +33 1 55 91 78 00 
 

Portugal 
ratiopharm, Comércio e Indústria de Produtos 
Farmacêuticos, Lda 
Tel: +351 21 476 75 50 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
Teva Finland Oy 
Finnland 
Sími: +358 20 180 5900 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 2 57 26 79 11 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 02 89 17 98 1 
 

Suomi/Finland 
Teva Finland Oy 
Puh/Tel: +358 20 180 5900 
 

Κύπρος 
Teva Ελλάς Α.Ε., Ελλάδα 
Τηλ: +30 211 880 5000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB Teva Baltics filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977 628500 
 

 
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. 
 
 
7. Information for injecting yourself 
 
This section contains information on how to give yourself an injection of Ratiograstim. It is important 
that you do not try to give yourself the injection unless you have received special training from your 



51 

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 Ratiograstim 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 Ratiograstim; 
- 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 Ratiograstim? 
1. Try to self-inject at approximately the same time every day. 
2. Take your Ratiograstim 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 Ratiograstim. 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 
Ratiograstim 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 

Ratiograstim pre-filled syringe, alcohol wipes and the puncture-proof container). 
 
How do I prepare my Ratiograstim injection? 
Before you inject Ratiograstim 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 Ratiograstim that your doctor prescribed. 

4. Check again to make sure the correct dose of Ratiograstim is in the syringe. 
5. You can now use the pre-filled syringe. 
 
Where should I give my injection? 



52 

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 Ratiograstim 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. 
- 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 
 



53 

Ratiograstim does not contain any preservative. In view of the possible risk of microbial 
contamination, Ratiograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim. 
 
Ratiograstim 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, Ratiograstim 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, Ratiograstim 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. 



54 

Package leaflet: Information for the user 
 

Ratiograstim 30 MIU/0.5 mL solution for injection/ infusion 
Ratiograstim 48 MIU/0.8 mL solution for injection/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 Ratiograstim is and what it is used for 
2. What you need to know before you use Ratiograstim 
3. How to use Ratiograstim 
4. Possible side effects 
5. How to store Ratiograstim 
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 Ratiograstim is and what it is used for 
 
What Ratiograstim is 
Ratiograstim is a white blood cell growth factor (granulocyte colony stimulating factor) and belong to 
a group of medicines called cytokines. Growth factors are proteins that are produced naturally in the 
body but they can also be made using biotechnology for use as a medicine. Ratiograstim works by 
encouraging the bone marrow to produce more white blood cells 
What Ratiograstim is used for 
A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes 
your body less able to fight infection. Ratiograstim stimulates the bone marrow to produce new white 
cells quickly. 
 
Ratiograstim can be used 
- to increase the number of white blood cells after treatment with chemotherapy to help prevent 

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

infections. 
- before high-dose chemotherapy to make the bone marrow produce more stem cells which can be 

collected and given back to you after your treatment. These can be taken from you or from a 
donor. The stem cells will then go back into the bone marrow and produce blood cells. 

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

- in patients with advanced HIV infection which will help reduce the risk of infections 
 
2. What you need to know before you use Ratiograstim 
 
Do not use Ratiograstim 



55 

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

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

- have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, 
lips,tongue or other parts of the body, shortness of breath, wheezing or trouble breathing as 
these could be signs of a severe allergic reaction (hypersensitivity). 

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

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

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

- Inflammation of aorta (the large blood vessel which transports blood from the heart to the 
body) has been reported rarely in cancer patients and healthy donors. The symptoms can 
include fever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell 
your doctor if you experience those symptoms. 

 
Loss of response to filgrastim 
 
If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 
doctor will investigate the reasons why including whether you have developed antibodies which 
neutralise filgrastim’s activity. 
 
Your doctor may want to monitor you closely, see section 4 of the package leaflet. 
 
 
If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the 
blood (leukaemia, myelodysplastic syndrome [MDS]). You should talk to your doctor about your risks 
of developing cancers of the blood and what testing should be done. If you develop or are likely to 
develop cancers of the blood, you should not use Ratiograstim, unless instructed by your doctor. 
 
If you are a stem cell donor, you must be aged between 16 and 60 years. 
 
Take special care with other products that stimulate white blood cells 
 
Ratiograstim is one of a group of products that stimulate the production of white blood cells. Your 
healthcare professional should always record the exact product you are using. 
 
Other medicines and Ratiograstim 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
 
Pregnancy and breast-feeding 
Ratiograstim has not been tested in pregnant or breast-feeding women.  
 
Ratiograstim is not recommended during pregnancy. 



56 

 
It is important to tell your doctor if you: 

• are pregnant or breast-feeding 
• think you may be pregnant or  
• are planning to have a baby 

If you become pregnant during Ratiograstim treatment, please inform your doctor.. Unless your doctor 
directs you otherwise, you must stop breast-feeding if you use Ratiograstim 
 
Driving and using machines 
Ratiograstim may have a minor influence on your ability to drive and use machines. This medicine 
may cause dizziness. It is advisable to wait and see how you feel after using this medicine and before 
driving or operating machinery.  
Ratiograstim contains sorbitol 
This medicine contains 50 mg sorbitol in each mL. 
 
Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare 
genetic disorder, you (or your child) must not receive this medicine. Patients with HFI cannot break 
down fructose, which may cause serious side effects. You must tell your doctor before receiving this 
medicine if you (or your child) have HFI or if your child can no longer take sweet foods or drinks 
because they feel sick, vomit or get unpleasant effects such as bloating, stomach cramps or diarrhoea 
Ratiograstim contains sodiumThis medicine contains less than 1 mmol sodium (23 mg) per pre-
filled syringe, i.e. essentially ‘sodium-free’. 
 
 
3. How to use Ratiograstim 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
How is Ratiograstim given and much should I take? 
 
Ratiograstim is usually given as a daily injection into the tissue just under the skin (known as a 
subcutaneous injection). It can also be given as a daily slow injection into the vein (known as an 
intravenous infusion). The usual dose varies depending on your illness and weight. Your doctor will 
tell you how much Ratiograstim you should take. 
 
Patients having a bone marrow transplant after chemotherapy: 
You will normally receive your first dose of Ratiogratsim at least 24 hours after your chemotherapy 
and at least 24 hours after receiving your bone marrow transplant. 
 
You, or people caring for you, can be taught how to give subcutaneous injections so that you can 
continue your treatment at home. However, you should not attempt this unless you have been properly 
trained first by your health care provider. 
 
How long will I have to take Ratiograstim? 
You will need to take Ratiograstim until your white blood cell count is normal. Regular blood tests 
will be taken to monitor the number of white blood cells in your body. Your doctor will tell you how 
long you will need to take Ratiograstim. 
 
 
Use in children  
Ratiograstim is used to treat children who are receiving chemotherapy or who suffer from severe low 
white blood cell count (neutropenia). The dosing in children receiving chemotherapy is the same as for 
adults. 
 
 
If you use more Ratiograstim than you should 



57 

Do not increase the dose your doctor has given you. If you use more Ratiograstim than you should, 
contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Ratiograstim 
If you have missed an injection, or injected too little, contact your doctor as soon as possible. Do not 
take a double dose to make up for any missed doses. 
 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Important side effects 
It is important to contact your doctor immediately 
- if you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face lips, 
mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea). 
 
- if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of 

Acute Respiratory Distress Syndrome (ARDS). 
- if you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients 

who received filgrastim. Call your doctor right away if you experience puffiness in your face or 
ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual. 

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 condition called “capillary leak syndrome”, which causes blood to 
leak from the small blood vessels into your body and needs urgent medical attention. 

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

- fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, shortness 
of breath, extreme pain or discomfort and clammy or sweaty skin. 

These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 
severe infection with whole-body inflammatory response which can be life threatening and 
needs urgent medical attention. 

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

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

 
A common side effect of Ratiograstim use is pain in your muscles or bones (musculoskeletal pain), 
which could be relieved by taking standard pain relief medicines (analgesics). In patients undergoing a 
stem cell or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of 
the donor cells against the patient receiving the transplant; signs and symptoms include rash on the 
palms of your hands or soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your 
eyes, lungs, vagina and joints. 
 
In normal stem cell donors an increase in white blood cells (leukocytosis) and a decrease of platelets 
may be seen this reduces the ability of your blood to clot (thrombocytopenia), these will be monitored 
by your doctor. 
 



58 

 
You may experience the following side effects: 
 
 
Very common (may affect more than 1 in 10 people): 

• decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 
• low red blood cell count (anaemia) 
• headache 
• diarrhoea 
• vomiting 
• nausea 
• unusual hair loss or thinning (alopecia) 
• tiredness (fatigue) 
• soreness and swelling of the digestive tract lining which runs from the mouth to the anus 

(mucosal inflammation) 
• fever (pyrexia) 

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

• inflammation of the lung (bronchitis) 
• upper respiratory tract infection 
• urinary tract infection 
• decreased appetite 
• trouble sleeping (insomnia) 
• dizziness 
• decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 
• tingling or numbness of the hands or feet (paraesthesia) 
• low blood pressure (hypotension) 
• high blood pressure (hypertension) 
• cough 
• coughing up blood (haemoptysis) 
• pain in your mouth and throat (oropharyngeal pain) 
• nose bleeds (epistaxis) 
• constipation 
• oral pain 
• enlargement of the liver (hepatomegaly) 
• rash 
• redness of the skin (erythema) 
• muscle spasm 
• pain when passing urine (dysuria) 
• chest pain 
• pain 
• generalised weakness (asthenia) 
• generally feeling unwell (malaise) 
• swelling in the hands and feet (oedema peripheral) 
• increase of certain enzymes in the blood 
• changes in blood chemistry 
• transfusion reaction 

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

• -  
• increase in white blood cells (leukocytosis) 
• allergic reaction (hypersensitivity) 
• rejection of transplanted bone marrow (graft versus host disease) 
• high uric acid levels in the blood, which may cause gout (hyperuricaemia) (blood uric acid 



59 

increased) 
• liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 
• lungs do not function as they should, causing breathlessness (respiratory failure) 
• swelling and/or fluid in the lungs (pulmonary oedema) 
• inflammation of the lungs (interstitial lung disease) 
• abnormal x-rays of the lungs (lung infiltration) 
• bleeding from the lung (pulmonary haemorrhage) 
• lack of absorption of oxygen in the lung (hypoxia) 
• bumpy skin rash (rash macuo-papular) 
• disease which causes bones to become less dense, making them weaker, more brittle and 

likely to break (osteoporosis) 
• injection site reaction 

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

• severe pain in the bones, chest, gut or joints (sickle cell anaemia with crisis) 
• sudden life-threatening allergic reaction (anaphylactic reaction) 
• pain and swelling of the joints, similar to gout (pseudogout) 
• a change in how your body regulates fluids within your body and may result in puffiness (fluid 

volume disturbances) 
• inflammation of the blood vessels in the skin (cutaneous vasculitis) 
• plum-coloured, raised, painful sores on the limbs and sometimes the face and neck with a 

fever (Sweets syndrome) 
• worsening of rheumatoid arthritis 
• unusual change in the urine 
• bone density decreased 
• Inflammation of aorta (the large blood vessel which transports blood from the heart to the 

body), see section 2 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Ratiograstim 
 
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 Ratiograstim contains 
- The active substance is filgrastim. Each mL of solution for injection/infusion contains 

60 million international units [MIU] (600 microgram) of filgrastim. 



60 

Ratiograstim 30 MIU/0.5 mL: Each pre-filled syringe contains 30 million international units 
[MIU] (300 microgram) of filgrastim in 0.5 mL solution. 
Ratiograstim 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 Ratiograstim looks like and contents of the pack 
Ratiograstim is a solution for injection/infusion in a pre-filled syringe with or without safety device. 
Ratiograstim is a clear and colourless solution. Each pre-filled syringe contains either 0.5 mL or 
0.8 mL of solution. 
 
Ratiograstim 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 
ratiopharm GmbH 
Graf-Arco-Straße 3 
89079 Ulm 
Germany 
 
Manufacturer 
Teva Biotech GmbH 
Dornierstraße 10 
89079 Ulm 
Germany 
 
Merckle GmbH 
Graf-Arco-Strasse 3 
89079 Ulm 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A./AG 
Tél/Tel: +32 3 820 73 73 
 

Lietuva 
UAB Teva Baltics 
Tel: +370 5 266 0203 
 

България 
Актавис ЕАД 
Teл: +359 2 489 95 85 
 

Luxembourg/Luxemburg 
ratiopharm GmbH 
Allemagne/Deutschland 
Tél/Tel: +49 731 402 02 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel.: +36 1 288 64 00 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Teva Pharmaceuticals Ireland 
L-Irlanda 
Tel: +353 19630330 
 

Deutschland 
ratiopharm GmbH 
Tel: +49 731 402 02 
 

Nederland 
Teva Nederland B.V. 
Tel: +31 800 0228 400 
 



61 

Eesti 
UAB Teva Baltics Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 211 880 5000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1 97 007 
 

España 
Teva Pharma, S.L.U. 
Tél: +34 91 387 32 80 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 22 345 93 00 
 

France 
Teva Santé 
Tél: +33 1 55 91 78 00 
 

Portugal 
ratiopharm, Comércio e Indústria de Produtos 
Farmacêuticos, Lda 
Tel: +351 21 476 75 50 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
Teva Finland Oy 
Finnland 
Sími: +358 20 180 5900 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 2 57 26 79 11 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 02 89 17 98 1 
 

Suomi/Finland 
Teva Finland Oy 
Puh/Tel: +358 20 180 5900 
 

Κύπρος 
Teva Ελλάς Α.Ε., Ελλάδα 
Τηλ: +30 211 880 5000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB Teva Baltics filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977 628500 
 

 
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. 
 
 
7. Information for injecting yourself 
 
This section contains information on how to give yourself an injection of Ratiograstim. 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 Ratiograstim myself? 



62 

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 Ratiograstim; 
- alcohol wipes or similar. 
 
What should I do before I give myself a subcutaneous injection of Ratiograstim? 
1. Try to self-inject at approximately the same time every day. 
2. Take your Ratiograstim 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 Ratiograstim. 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 
Ratiograstim 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 

Ratiograstim pre-filled syringe and alcohol wipes). 
 
How do I prepare my Ratiograstim injection? 
Before you inject Ratiograstim 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 Ratiograstim that your doctor prescribed. 

4. Check again to make sure the correct dose of Ratiograstim 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). 
 



63 

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 
 

7 8 
 
Remember 
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice. 



64 

 
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 
 
Ratiograstim does not contain any preservative. In view of the possible risk of microbial 
contamination, Ratiograstim syringes are for single use only. 
 
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim. 
 
Ratiograstim 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, Ratiograstim 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, Ratiograstim 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. 


	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