Accofil
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of solution contains 60 million units (MU) (equivalent to 600 micrograms [μg]) of filgrastim.  
 
Each pre-filled syringe contains 30 MU (equivalent to 300 micrograms of filgrastim in 0.5 ml solution 
for injection or infusion. 
 
Filgrastim is a recombinant methionyl human granulocyte-colony stimulating factor produced in 
Escherichia coli (BL21) by recombinant DNA technology. 
 
Excipient with known effect  
 
Each ml of solution contains 50 mg of sorbitol (E420) 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection or infusion  
 
Clear, colourless solution 
 
 
4. CLINCAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Accofil 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 Accofil are similar in adults and children receiving cytotoxic chemotherapy.  
 
Accofil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs). 
 
In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute 
neutrophil count (ANC) of ≤ 0.5 x 109/L, and a history of severe or recurrent infections, long term 
administration of Accofil is indicated to increase neutrophil counts and to reduce the incidence and 
duration of infection-related events. 
 
Accofil 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 
 
Accofil 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 



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with an oncology-haematology centre with acceptable experience in this field and where the 
monitoring of haematopoietic progenitor cells can be correctly performed.  
 
Posology  
 
Established cytotoxic chemotherapy  
The recommended dose of filgrastim is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of 
Accofil should not be administered less than 24 hours following cytotoxic chemotherapy. In 
randomised clinical trials, a subcutaneous dose of 230 microgram/m2/day (4.0 to 8.4 
microgram/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 
1-2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim 
therapy should not be discontinued before the expected nadir has passed and the neutrophil count has 
recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to the time of the 
expected neutrophil nadir, is not recommended.  
 
In patients treated with myeloablative therapy followed by bone marrow transplantation  
The recommended starting dose of filgrastim is 1.0 MU/kg/day (10 micrograms/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 MU (5µg) /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 
 
For mobilisation of peripheral blood progenitor cells (PBPC) in patients undergoing 
myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation  
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MU (10 
µg)/kg/day for 5-7 consecutive days. The timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 
6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Filgrastim 
dosing should be maintained until the last leukapheresis.  
 
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 
0.5 MU (5 µg)/kg/day given daily from the first day after completion of chemotherapy until the 
expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. 
Leukapheresis should be performed during the period when the ANC rises from  
< 0.5 x 109/L to > 5.0 x 109/L. For patients who have not had extensive chemotherapy, one 
leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended. 
 
For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation  



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For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MU (10 µg)/kg/day 
for 4 - 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if 
needed in order to collect 4 x 106

 
CD34+ cells/kg recipient bodyweight.  

 
In patients with severe chronic neutropenia (SCN)  
Congenital neutropenia 
The recommended starting dose is 1.2 MU (12 µg)/kg/day as a single dose or in divided doses.  
 
Idiopathic or cyclic neutropenia 
The recommended starting dose is 0.5 MU (5 µg)/kg/day as a single dose or in divided doses.  
 
Dose adjustments 
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has 
reached and can be maintained at more than 1.5 x 109/L. When the response has been obtained, the 
minimal effective dose to maintain this level should be established. Long-term daily administration is 
required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose 
may be doubled or halved depending upon the patient's response. Subsequently, the dose may be 
individually adjusted every 1-2 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 studies, 97% of patients who responded had a complete response at doses 
of ≤ 24 µg/kg/day. The long-term safety of administration of filgrastim at doses above 24 µg/kg/day) 
in patients with SCN has not been established.  
 
In patients with HIV infection  
For reversal of neutropenia  
The recommended starting dose of filgrastim is 0.1 MU (1 µg)/kg/day, with titration up to a maximum 
of 0.4 MU (4 µg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC > 2.0 
x 109/L). In clinical studies, more than 90% of patients responded at these doses, achieving a reversal 
of neutropenia in a median of 2 days.  
 
In a small number of patients (< 10%), doses up to 1.0 MU(10 µg)/kg/day were required to achieve 
reversal of neutropenia. 
 
For maintenance of normal neutrophil counts  
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal 
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MU 
(300 µg)/day is recommended. Further dose adjustment may be necessary, as determined by the 
patient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical studies, dosing with 30 
MU (300 µg)/day on 1 - 7 days per week was required to maintain the ANC > 2.0 x 109/L, with the 
median dose frequency being 3 days per week. Long-term administration may be required to maintain 
the ANC > 2.0 x 109/L.  
 
Special population 
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 posology recommendations cannot be made. 
 
Patients with renal impairment  
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it 
exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. 
Dose adjustment is not required in these circumstances.  
 
Paediatric patients in the SCN and cancer settings  
Sixty-five percent of patients studied in a SCN trial program were under 18 years of age. The efficacy 
of the treatment was clear for this age group, which included most patients with congenital 
neutropenia. There were no differences in the safety profiles for paediatric patients treated for SCN. 
 



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Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are 
similar in both adults and children receiving cytotoxic chemotherapy. 
 
The dosage recommendations in paediatric patients are the same as those in adults receiving 
myelosuppressive cytotoxic chemotherapy. 
 
Method of administration  
 
Established cytotoxic chemotherapy  
Filgrastim may be administered as a daily subcutaneous injection or alternatively as a daily 
intravenous infusion diluted in glucose 50 mg/ml (5%) solution over 30 minutes. For further 
instructions on dilution prior to infusion 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.  
 
Patients treated with myeloablative therapy followed by bone marrow transplantation  
Filgrastim is administered as an intravenous short-term infusion over 30 minutes or as a subcutaneous 
or intravenous continuous infusion over 24 hours, in each case after dilution in 20 ml of glucose 50 
mg/ml (5%) solution. For further instructions on dilution with glucose 50 mg/ml (5%) solution prior to 
infusion see section 6.6.  
 
In patients with mobilisation of PBPC  
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 20ml of 5% glucose solution (see section 6.6).  
 
Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy 
Filgrastim should be given by subcutaneous injection. 
 
Filgrastim for PBPCs for mobilisation in normal donors prior to allogeneic PBPC transplantation 
Filgrastim should be given by subcutaneous injection. 
 
In patients with SCN 
For congenital, idiopathic or cyclic neutropenia, filgrastim should be given by subcutaneous injection. 
 
In patients with HIV infection  
For the reversal of neutropenia and maintenance of normal neutrophil counts in patients with HIV 
infection, filgrastim is administered subcutaneously.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade 
name of the administered product should be clearly recorded in the patient file.  
 
Special warnings and precautions across indications 
 
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established 
dosage regimens. 
 
Filgrastim should not be administered to patients with severe congenital neutropenia who develop 



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leukaemia or have evidence of leukaemic evolution. 
 
Hypersensitivity 
Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have 
been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with 
clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of 
hypersensitivity to filgrastim or pegfilgrastim.  
 
Immunogenicity 
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of 
antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all 
biologics; however, they have not been associated with neutralising activity at present. 
  
Special precautions in patients with acute myeloid leukaemia (AML) 
 
Malignant cell growth 
G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some non-
myeloid cells in vitro. 
 
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. Therefore, 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. 
 
Other special precautions 
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. 
 
Pulmonary adverse effects 
Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF 
administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher 
risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological 
signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of 
Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and appropriate 
treatment given in these cases. 
 
Capillary leak syndrome 
Capillary leak syndrome has been reported after granulocyte colony-stimulating factor administration, 
and is characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Patients 
who develop symptoms of capillary leak syndrome should be closely monitored and receive standard 
symptomatic treatment, which may include a need for intensive care (see section 4.8). 
 
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. 
 



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Special precautions in cancer patients 
 
Splenomegaly and splenic rupture 
Cases of splenomegaly and splenic rupture have been reported uncommonly following administration 
of filgrastim. Some cases of splenic rupture were fatal. Individuals receiving filgrastim who report left 
upper abdominal and/ or shoulder tip pain should be evaluated for an enlarged spleen or splenic 
rupture. 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. 
 
Leukocytosis 
White blood cell counts of 100 x 109/L or greater have been observed in less than 5% of patients 
receiving filgrastim at doses above 0.3 MIU/kg/day (3 µg/kg/day). No undesirable effects directly 
attributable to this degree of leukocytosis have been reported. However, in view of the potential risks 
associated with severe leukocytosis, a white blood cell count should be performed at regular intervals 
during filgrastim therapy. If leukocyte counts exceed 50 x 109/L after the expected nadir, filgrastim 
should be discontinued immediately. However, during the period of administration of filgrastim for 
PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Risks associated with increased doses of chemotherapy 
Special caution should be used when treating patients with high dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may 
lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please 
refer to the prescribing information of the specific chemotherapy agents used). 
 
Effect of chemotherapy on erythrocytes and thrombocytes 
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to 
myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy 
(e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and 
anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should 
be taken when administering single or combination chemotherapeutic agents which are known to 
cause severe thrombocytopenia. 
 
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of 
thrombocytopenia following myelosuppressive or myeloablative chemotherapy. 
 
Other special precautions 
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been 
studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil 
counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such 
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 
by tumour). 
 
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 
reported occasionally in patients undergoing high dose chemotherapy followed by transplantation. 
 
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF 
after allogeneic bone marrow transplantation (see section 4.8 and 5.1). 
 
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been 
associated with transient abnormal bone scans. This should be considered when interpreting bone-
imaging results. 
 
Special precautions in patients undergoing PBPC mobilization 
 
Mobilization of PBPC 



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There are no prospectively randomised comparisons of the two recommended mobilisation methods 
(filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patient 
population. The degree of variation between individual patients and between laboratory assays of 
CD34+ cells mean that direct comparison between different studies is difficult. It is therefore difficult 
to recommend an optimal method. The choice of mobilisation method should be considered in relation 
to the overall objectives of treatment for an individual patient.  
 
Prior exposure to cytotoxic agents 
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient 
mobilisation of PBPC to achieve the recommended minimum yield (2.0 x 106 CD34+ cells/kg) or 
acceleration of platelet recovery to the same degree. 
 
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may 
adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and 
carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation, 
may reduce progenitor yield. However, the administration of melphalan, carboplatin or carmustine 
(BCNU) together with filgrastim has been shown to be effective for progenitor mobilisation. When 
peripheral blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell 
mobilization procedure early in the treatment course of the patient. Particular attention should be paid 
to the number of progenitors mobilised in such patients before the administration of high-dose 
chemotherapy. If yields are inadequate, as measured by the criteria above, alternative forms of 
treatment not requiring progenitor support should be considered. 
 
Assessment of progenitor cell yields 
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular 
attention should be paid to the method of quantitation. The results of flow cytometric analysis of 
CD34+ cell numbers vary depending on the precise methodology used and therefore, recommendations 
of numbers based on studies in other laboratories need to be interpreted with caution. 
 
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of 
platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. 
 
The recommendation of a minimum yield of ≥ 2.0 x 106 CD34+ cells/kg is based on published 
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield 
appear to correlate with more rapid recovery; those below with slower recovery. 
 
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilization 
 
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. Particular attention should be paid to haematological values 
and infectious diseases. The safety and efficacy of filgrastim has not been assessed in normal donors 
less than 16 years or greater than 60 years of age.  
 
Thrombocytopenia 
Thrombocytopenia has been reported very commonly in patients receiving filgrastim .Platelet counts 
should therefore be monitored closely.  
 
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 are < 75 x 109/L.  
 
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 



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in haemostasis. Filgrastim administration should be discontinued or its dosage should be reduced if the 
leukocyte counts rise to > 70 x 109/L. Donors who receive G-CSFs for PBPC mobilisation should be 
monitored until haematological indices return to normal.  
 
Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The 
significance of these changes is unknown. Nevertheless, a risk of promotion of a malignant myeloid 
clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and 
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 
 
Common but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of 
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical 
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or 
patients reporting left upper abdominal pain or shoulder tip pain.  
 
In normal donors, dyspnoea has been reported commonly and other pulmonary adverse events 
(haemoptysis, pulmonary haemorrhage, lung infiltrates, and hypoxia) have been reported 
uncommonly. In case of suspected or confirmed pulmonary adverse events, discontinuation of 
treatment with filgrastim should be considered and appropriate medical care given.  
 
Special precautions in recipients of allogeneic PBPC mobilised with filgrastim 
 
Current data indicate that immunological interactions between the allogeneic PBPC graft and the 
recipient may be associated with an increased risk of acute and chronic GvHD when compared with 
bone marrow transplantation. 
 
Special precautions in SCN patients 
 
Blood cell counts 
Thrombocytopenia has been reported commonly in patients receiving filgrastim. Platelet counts should 
be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should 
be given to intermittent cessation or decreasing the dose of filgrastim in patients who develop 
thrombocytopenia, i.e. platelets consistently < 100,000/mm3. 
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 
which require close monitoring of cell counts. 
 
Transformation to leukaemia or myelodysplastic syndrome 
Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic 
disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell 
counts with differential and platelet counts and an evaluation of bone marrow morphology and 
karyotype should be performed prior to treatment. 
 
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in 
clinical trial patients with SCN treated with filgrastim. This observation has only been made in 
patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease 
and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had 
normal cytogenetic evaluations at baseline was subsequently found to have abnormalities, including 
monosomy 7, on routine repeat evaluation. If patients with SCN develop abnormal cytogenetics, the 
risks and benefits of continuing filgrastim should be carefully weighed; filgrastim should be 
discontinued if MDS or leukaemia occurs. 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. 



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Cases of splenomegaly have been reported very commonly and cases of splenic rupture have been 
reported commonly following administration of filgrastim. Individuals receiving filgrastim who report 
left upper abdominal and/ or shoulder tip pain should be evaluated for an enlarged spleen or splenic 
rupture. 
 
 Splenomegaly is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of patients in 
studies were documented as having palpable splenomegaly. Increases in volume, measured 
radiographically occurred early during filgrastim therapy and tended to plateau later in treatment. Dose 
reductions were noted to slow or stop the progression of splenic enlargement and in 3% of patients a 
splenectomy was required. Spleen size should be evaluated regularly. Abdominal palpation should be 
sufficient to detect abnormal increases in splenic volume. 
 
Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis 
should be performed to monitor this event. 
 
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 
established. 
 
Special precautions in patients with HIV infection 
 
Cases of splenomegaly have been reported  commonly following administration of filgrastim. 
Individuals receiving filgrastim who report left upper abdominal and/ or shoulder tip pain should be 
evaluated for an enlarged spleen or splenic rupture. 
 
Blood cell counts 
ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Some 
patients may respond very rapidly and with a considerable increase in neutrophil count to the initial 
dose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of 
filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice 
weekly for the first two weeks and subsequently once per week or once every other week during 
maintenance therapy. During intermittent dosing with 30 MU (300 microgram)/day of filgrastim, there 
can be wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or 
nadir ANC, it is recommended that blood samples are taken for ANC measurement immediately prior 
to any scheduled dosing with filgrastim. 
 
Risk associated with increased doses of myelosuppressive 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. 
 
Special precautions in sickle cell trait and sickle cell disease 
 
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with 
sickle cell trait or sickle cell disease. Physicians should exercise caution when considering the use of 
filgrastim in patients with sickle cell trait or sickle cell disease and only after careful evaluation of the 
potential risks and benefits. 
 
All patients 



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Accofil contains sorbitol (E420) as an excipient at a concentration of 50 mg/ml. Patients with rare 
hereditary problems of fructose intolerance should not use this medicinal product. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxic 
chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing 
myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended 
in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small 
number of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severity 
of neutropenia may be exacerbated. 
 
Possible interactions with other haematopoietic growth factors and cytokines have not yet been 
investigated in clinical trials. 
 
Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. 
Although this interaction has not been formally investigated, there is no evidence that such an 
interaction is harmful. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited 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 or its metabolites are excreted in human milk. A risk to the breast-
feeding child 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 
 
Accofil may have a minor influence on the ability to drive and use machines.  
 
Dizziness may occur following the administration of Accofil (see section 4.8). 
 
4.8 Undesirable effects 



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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. 
 
Tabulated list 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.  
 
The assessment of undesirable effects is based on the following frequency data:  
 
Very common: ≥ 1/10  
Common: ≥ 1/100 to < 1/10  
Uncommon: ≥ 1/1,000 to < 1/100  
Rare: ≥ 1/10,000 to < 1/1,000  
Very rare: < 1/10,000  
 
Not known: cannot be estimated from the available data. 
 

MedDRA 
system 
organ class 

Adverse reactions 
Very common Common Uncommon Rare Ver

y 
rare  
 

Not 
know
n 

Infections 
and 
infestations 

 Sepsis 
Bronchitis 
Upper 
respiratory 
tract infection 
Urinary tract 
infection 

  - - 

Blood and 
lymphatic 
system 
disorders 

Thrombocytopenia 
Anaemiae 

Splenomegalya 
Haemoglobin 
decreasede 

Leukocytosisa Splenic 
rupturea 
Sickle cell 
anaemia 
with crisis 

- - 

Immune 
system 
disorders 

  Graft versus 
Host Diseaseb 
Drug 
hypersensitivitya 
Hypersensitivity 

Anaphylact
ic 
reaction 

- - 

Metabolism 
and 
nutrition 
disorders 

 Decreased 
Appetitee 
Blood lactate 
dehydrogenase 
increased 

Hyperuricaemia 
Blood uric acid 
increased 

Blood 
glucose 
decreased 
Pseudogout
a 

- - 



13 
 

MedDRA 
system 
organ class 

Adverse reactions 
Very common Common Uncommon Rare Ver

y 
rare  
 

Not 
know
n 

(Chondroca
lcinosis 
Pyrophosp
hate) 
Fluid 
volume 
disturbance
s 

Psychiatric 
disorders 

 Insomnia   - - 

Nervous 
system 
disorders 

Headachea Dizziness, 
Hypoaesthesia, 
Paraesthesia 

  - - 

Vascular 
disorders 

 Hypotension 
Hypertension 

Veno-occlusive 
diseased 
 

Capillary 
leak 
syndromea 
,Aortitis 

- - 

Respiratory
, thoracic 
and 
mediastinal 
disorders 

 Haemoptysis 
Dyspnoea 
Cougha 
Oropharyngeal 
paina,e 
Epistaxis 

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

 - - 

Gastrointes
tinal 
disorders 

Diarrhoeaa,e  
Vomitinga,e  
Nauseaa 

Constipatione 
Oral pain 

  - - 

Hepatobilia
ry disorders 

 Blood alkaline 
phosphatase 
increased 
Hepatomegaly 

Gamma-
glutamyl 
transferase 
increased  
Aspartate 
aminotransferas
e 
increased 

 - - 

Skin and 
subcutaneo
us tissue 
disorders 

Alopeciaa 
 

Rasha  
Erythema 

Rash 
maculopapular 

Sweets 
syndrome 
(acute 
febrile 
neutrophili
c 
dermatosis) 

- - 



14 
 

MedDRA 
system 
organ class 

Adverse reactions 
Very common Common Uncommon Rare Ver

y 
rare  
 

Not 
know
n 

 Cutaneous 
vasculitisa 

Musculoske
letal and 
connective 
tissue 
disorders 

Musculoskeletal 
painc 

Muscle spasms Osteoporosis Bone 
density 
decreased 
Exacerbati
on of 
rheumatoid 
arthritis 

- - 

Renal and 
urinary 
disorders 

 Dysuria 
Haematuria 

Proteinuria Urine 
abnormalit
y 
Glomerulo
nephritis 

- - 

General 
disorders 
and 
administrat
ion site 
conditions 

Fatiguea  
Mucosal 
inflammationa 
Pyrexia 

Chest paina 
Astheniaa  
Paina 
Malaisee 
Oedema 
peripherale 

Injection site 
reaction 

 - - 

Injury, 
poisoning 
and 
procedural 
complicatio
ns 

 Transfusion 
reactione 

  - - 

 

a See section 4.8, Description of selected adverse reactions  
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow 
transplantation (see section 4.8, Description of selected adverse reactions)  
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, 
musculoskeletal chest pain, neck pain  
d Cases were observed in the post-marketing setting with filgrastim 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 
 
Description of selected adverse reactions 
 
GvHD 
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see sections 4.4 and 5.1). 
 
Capillary leak syndrome 
Cases of capillary leak syndrome have been reported in the post marketing setting 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). 
 
In randomised, placebo-controlled clinical studies, filgrastim did not increase the incidence of 
undesirable effects associated with cytotoxic chemotherapy. In those clinical trials, undesirable effects 
reported with equal frequency in cancer patients treated with filgrastim/chemotherapy and 



15 
 

placebo/chemotherapy included nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, 
headache, cough, skin rash, chest pain, generalised weakness, sore throat, constipation and pain. 
 
In the post-marketing setting cutaneous vasculitis has been reported in patients treated with filgrastim. 
The mechanism of vasculitis in patients receiving filgrastim is unknown. The frequency is estimated 
as uncommon from clinical trial data.  
 
Sweets syndrome 
Cases of Sweets syndrome (acute febrile dermatosis) have been reported in the post-marketing setting. 
The frequency is estimated as uncommon from clinical trial data.  
 
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 uncommonly following administration 
of filgrastim. Some cases of splenic rupture were fatal (see section 4.4). 
 
Hypersensitivity 
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and 
hypotension occurred on initial or subsequent treatment in clinical studies and in post-marketing 
experience. Overall, reports were more common after intravenous administration. In some cases, 
symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be 
permanently discontinued in patients who experience a serious allergic reaction.  
 
In the post-marketing setting, isolated cases of sickle cell crises have been reported in patients with 
sickle cell disease (see section 4.4). The frequency is estimated as uncommon from clinical trial data. 
 
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. 
 
Pseudogout (chondrocalcinosis pyrophosphate) 
Pseudogout has been reported in cancer patients treated with filgrastim, and the frequency is estimated 
as uncommon from clinical trial data. 
 
Leukocytosis 
Leukocytosis (WBC > 50 x 109/L) was observed in 41% of donors and transient thrombocytopenia 
(platelets < 100 x 109/L) following filgrastim treatment and leukapheresis was observed in 35% of 
donors.  
 
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. 
 
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 



16 
 

experience has not identified differences in the responses between elderly and younger adult patients. 
There are insufficient data to evaluate Accofil use in geriatric subjects for other approved Accofil 
indications.  
 
Paediatric SCN patients 
Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe 
chronic neutropenia receiving chronic treatment with filgrastim.  
  
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The effects of Accofil overdose have not been established. Discontinuation of filgrastim therapy 
usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal 
levels in 1 to 7 days. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: immunostimulants, colony stimulating factors, ATC code: L03AA02 
Accofil is a biosimilar medicinal product. Detailed information is available on the website of the 
European Medicines Agency http://www.ema.europa.eu.  
 
Pharmacodynamic effects 
 
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils 
from the bone marrow. Accofil containing r-metHuG-CSF (filgrastim) causes marked increases in 
peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some SCN 
patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and 
basophils relative to baseline; some of these patients may present with eosinophilia or basophilia 
already prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. 
Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by 
tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating 
neutrophil counts decrease by 50% within 1 to 2 days, and to normal levels within 1 to 7 days.  
 
Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the 
incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim 
significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after 
induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone 
marrow transplantation. The incidence of fever and documented infections were not reduced in either 
setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed 
by bone marrow transplantation.  
 
Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into 
peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic 
therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs 
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.  

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


17 
 

 
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 
(BM) transplantation 

Publication  Period of 
Study  

N  Acute Grade          
II - IV GvHD  

Chronic 
GvHD  

TRM  

Meta-Analysis  (2003)  1986 - 
2001

a 
 

1198  1.08 
(0.87, 1.33)  

1.02 
(0.82, 1.26)  

0.70 
(0.38, 1.31)  

European Retrospective 
Study (2004)  

1992 - 
2002

b 
 

1789  1.33 
    (1.08, 1.64)  

1.29 
(1.02, 1.61)  

1.73 
(1.30, 2.32)  

International Retrospective  
Study (2006)  

1995 - 
2000

b 
 

2110  1.11 
  (0.86, 1.42)  

1.10 
(0.86, 1.39)  

1.26 
(0.95, 1.67)  

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

b
Analysis includes patients receiving BM transplant during this period  

 
Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC 
transplantation  
In normal donors, a 10 micrograms/kg/day dose administered subcutaneously for 4 - 5 consecutive 
days allows a collection of ≥ 4 x 106 

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

donors after two leukaphereses.  
 
Use of filgrastim in adults with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a 
sustained increase in ANCs in peripheral blood and a reduction of infection and related events.  
 
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled 
dosing of antiviral and/or other myelosuppressive treatments. There is no evidence that patients with 
HIV infection treated with filgrastim show an increase in HIV replication. 
 
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on 
human endothelial cells. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following subcutaneous administration of recommended doses, serum concentrations were maintained 
above10 ng/ml for 8 - 16 hours.  
 
Distribution  
 
The volume of distribution in blood is approximately 150 ml/kg.  
 
Elimination  
 
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous 
or 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 Accofil over a period 
of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no 
evidence of drug accumulation and comparable half-lives.  



18 
 

 
Linearity 
 
There is a positive linear correlation between the dose and the serum concentration of filgrastim, 
whether administered intravenously or subcutaneously. Following subcutaneous administration of 
recommended doses , serum concentrations were maintained above 10ng/ml for 8 to 16 hours. The 
volume of distribution in blood is approximately 150ml/kg. 
 
5.3 Preclinical safety data 
 
Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed 
changes attributable to the expected pharmacological actions including increases in leukocytes, 
myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These 
changes all reversed after discontinuation of treatment.  
Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous (80 
µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally 
toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size 
and fetal weight were observed.  
Based on reported data for another filgrastim product similar to Accofil, comparable findings plus 
increased fetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which 
corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients 
treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level for embryo-fetal 
toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of approximately 
3-5 times the exposures observed in patients treated with the clinical dose.  
In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of 
rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external 
differentiation and growth retardation (≥20 µg/kg/day) and slightly reduced survival rate (100 
µg/kg/day).  
Filgrastim had no observed effect on the fertility of male or female rats.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Acetic acid glacial 
Sodium hydroxide 
Sorbitol (E420)  
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Accofil must not be diluted with sodium chloride solutions.  
 
Diluted filgrastim may be adsorbed to glass and plastic materials. 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.  
 
6.3 Shelf life 
 
3 years. 
 
Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 
24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 



19 
 

responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless 
dilution has taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). Do not freeze.  
 
Accidental one-time exposure to freezing temperatures does not adversely affect the stability of Accofil. If 
exposure has been greater than 24 hours or frozen more than once then Accofil should NOT be used. 
 
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from 
the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 
days. At the end of this period, the product should not be put back in the refrigerator and should be 
disposed of. 
 
Keep the syringe in the outer carton in order to protect from light. 
 
For storage conditions of the diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass pre-filled syringe with a permanently attached stainless steel needle in the tip and 1/40 
printed markings for graduations from 0.1 mL to 1 mL on the barrel. The needle cover of the pre-filled 
syringe contains dry natural rubber (see section 4.4). Each pre-filled syringe contains 0.5 ml solution. 
 
Each pack contains one, three, five, seven or ten pre-filled syringes, with or without a needle safety 
guard, and alcohol swab(s). The packs without blister are for syringes without needle safety guard. 
The blister packs are for individual syringes with prefixed needle safety guard.  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
If required, Accofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 
(2 µg) per ml is not recommended at any time. 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used. Do not shake.  
 
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per ml, human 
serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final 
injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 µg) should be given with 0.2 
ml of 200 mg/ml (20%) human albumin solution added. 
 
Accofil contains no preservative. In view of the possible risk of microbial contamination, Accofil  
pre-filled syringes are for single use only. 
 
When diluted in 5% glucose, Accofil is compatible with glass and a variety of plastics including PVC, 
polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 
 
Using the pre-filled syringe with a needle safety guard  
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 
plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger.  



20 
 

 
Using the pre-filled syringe without a needle safety guard  
 
Administer the dose as per standard protocol. 
 
Disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/001 
EU/1/14/946/002 
EU/1/14/946/005 
EU/1/14/946/006 
EU/1/14/946/007 
EU/1/14/946/008 
EU/1/14/946/009 
EU/1/14/946/010 
EU/1/14/946/017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 18.09.2014 
Date of latest renewal: 12th June 2019 
 
 
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 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 48 MU/0.5 ml solution for injection or infusion in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of solution contains 96 million units (MU) (equivalent to 960 micrograms [μg]) of filgrastim.  
 
Each pre-filled syringe contains 48 MU (equivalent to 480 micrograms of filgrastim in 0.5 ml solution 
for injection or infusion. 
 
Filgrastim is a recombinant methionyl human granulocyte-colony stimulating factor produced in 
Escherichia coli (BL21) by recombinant DNA technology. 
 
Excipient with known effect 
 
Each ml of solution contains 50 mg of sorbitol (E420) 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection or infusion  
 
Clear, colourless solution 
 
 
4. CLINCAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Accofil 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 Accofil are similar in adults and children receiving cytotoxic chemotherapy.  
 
Accofil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs). 
 
In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute 
neutrophil count (ANC) of ≤ 0.5 x 109/L, and a history of severe or recurrent infections, long term 
administration of Accofil is indicated to increase neutrophil counts and to reduce the incidence and 
duration of infection-related events. 
 
Accofil 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 
 
Accofil 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 



22 
 

with an oncology-haematology centre with acceptable experience in this field and where the 
monitoring of haematopoietic progenitor cells can be correctly performed.  
 
Posology  
 
Established cytotoxic chemotherapy  
The recommended dose of filgrastim is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of 
Accofil should not be administered less than 24 hours following cytotoxic chemotherapy. In 
randomised clinical trials, a subcutaneous dose of 230 microgram/m2/day (4.0 to 8.4 
microgram/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 
1-2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim 
therapy should not be discontinued before the expected nadir has passed and the neutrophil count has 
recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to the time of the 
expected neutrophil nadir, is not recommended.  
 
In patients treated with myeloablative therapy followed by bone marrow transplantation  
The recommended starting dose of filgrastim is 1.0 MU/kg/day (10 micrograms/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 MU (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 
 
For mobilisation of peripheral blood progenitor cells (PBPC) in patients undergoing 
myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation  
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MU (10 
µg)/kg/day for 5-7 consecutive days. The timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 
6 which is often sufficient. In other circumstances, additional leukaphereses may be necessary. 
Filgrastim dosing should be maintained until the last leukapheresis. 
 
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 
0.5 MU (5 µg)/kg/day given daily from the first day after completion of chemotherapy until the 
expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. 
Leukapheresis should be performed during the period when the ANC rises from  
< 0.5 x 109/L to > 5.0 x 109/L. For patients who have not had extensive chemotherapy, one 
leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended. 
  
For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation  



23 
 

For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MU (10 µg)/kg/day 
for 4 - 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if 
needed in order to collect 4 x 106

 
CD34+ cells/kg recipient bodyweight.  

 
In patients with severe chronic neutropenia (SCN)  
 
Congenital neutropenia 
The recommended starting dose is 1.2 MU (12 µg)/kg/day as a single dose or in divided doses.  
 
Idiopathic or cyclic neutropenia 
The recommended starting dose is 0.5 MU (5 µg)/kg/day as a single dose or in divided doses.  
 
Dose adjustments 
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has 
reached and can be maintained at more than 1.5 x 109/L. When the response has been obtained, the 
minimal effective dose to maintain this level should be established. Long-term daily administration is 
required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose 
may be doubled or halved depending upon the patient's response. Subsequently, the dose may be 
individually adjusted every 1-2 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 studies, 97% of patients who responded had a complete response at doses 
of ≤ 24 µg/kg/day. The long-term safety of administration of filgrastim at doses above 24 µg/kg/day in 
patients with SCN has not been established.  
 
In patients with HIV infection  
 
For reversal of neutropenia 
The recommended starting dose of filgrastim is 0.1 MU (1 µg )/kg/day given daily with titration up to 
a maximum of 0.4 MU (4 µg )/kg/day until a normal neutrophil count is reached and can be 
maintained (ANC > 2.0 x 109/L). In clinical studies, more than 90% of patients responded at these 
doses, achieving a reversal of neutropenia in a median of 2 days.  
In a small number of patients (< 10%), doses up to 1.0 MU (10 µg) /kg/day were required to achieve 
reversal of neutropenia. 
 
For maintenance of normal neutrophil counts 
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal 
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MU 
(300 µg)/day is recommended. Further dose adjustment may be necessary, as determined by the 
patient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical studies, dosing with 30 
MU (300 µg )/day on 1 - 7 days per week was required to maintain the ANC > 2.0 x 109/L, with the 
median dose frequency being 3 days per week. Long-term administration may be required to maintain 
the ANC > 2.0 x 109/L.  
 
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 posology recommendations cannot be made. 
 
Patients with renal impairment  
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it 
exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. 
Dose adjustment is not required in these circumstances.  
 
Paediatric patients in the SCN and cancer settings  
Sixty-five percent of patients studied in a SCN trial program were under 18 years of age. The efficacy 
of the 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. 



24 
 

 
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. 
 
Method of administration  
 
Established cytotoxic chemotherapy  
Filgrastim may be administered as a daily subcutaneous injection or alternatively as a daily 
intravenous infusion diluted in glucose 50 mg/ml (5%) solution over 30 minutes. For further 
instructions on dilution prior to infusion 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.  
 
Patients treated with myeloablative therapy followed by bone marrow transplantation  
Filgrastim is administered as an intravenous short-term infusion over 30 minutes or as a subcutaneous 
or intravenous continuous infusion over 24 hours, in each case after dilution in 20 ml of glucose 50 
mg/ml (5%) solution. For further instructions on dilution with glucose 50 mg/ml (5%) solution prior to 
infusion see section 6.6.  
 
In patients with mobilisation of PBPC  
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 20ml of 5% glucose solution (see section 6.6). 
 
Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy  
Filgrastim should be given by subcutaneous injection. 
 
Filgrastim for PBPC mobilisation  in normal donors prior to allogeneic PBPC transplantation  
Filgrastim should be given by subcutaneous injection.  
 
In patients with SCN 
For congenital, idiopathic or cyclic neutropenia, filgrastim should be given by subcutaneous injection. 
 
In patients with HIV infection  
For the reversal of neutropenia and maintenance of normal neutrophil counts in patients with HIV 
infection, filgrastim is administered subcutaneously.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade 
name of the administered product should be clearly recorded in the patient file.  
 
Special warnings and precautions across indications 
 
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established 
dosage regimens. 
 



25 
 

Filgrastim should not be administered to patients with severe congenital neutropenia who develop 
leukaemia or have evidence of leukaemic evolution. 
 
Hypersensitivity 
Hypersensitivity, including anaphylactic reactions ,occurring on initial or subsequent treatment have 
been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with 
clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of 
hypersensitivity to filgrastim or pegfilgrastim.  
 
Immunogenicity 
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of 
antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all 
biologics; however, they have not been associated with neutralising activity at present. 
  
Special precautions in patients with acute myeloid leukaemia (AML) 
 
Malignant cell growth 
G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some non-
myeloid cells in vitro. 
 
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. Therefore, 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. 
 
Other special precautions 
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. 
 
Pulmonary adverse effects 
Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF 
administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher 
risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological 
signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of 
Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and appropriate 
treatment given in these cases. 
 
Capillary leak syndrome 
Capillary leak syndrome has been reported after granulocyte colony-stimulating factor administration, 
and is characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Patients 
who develop symptoms of capillary leak syndrome should be closely monitored and receive standard 
symptomatic treatment, which may include a need for intensive care (see section 4.8). 
 
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. 
 



26 
 

Special precautions in cancer patients 
 
Splenomegaly and splenic rupture 
Cases of splenomegaly and splenic rupture have been reported uncommonly following administration 
of filgrastim. Some cases of splenic rupture were fatal. Individuals receiving filgrastim who report left 
upper abdominal and/ or shoulder tip pain should be evaluated for an enlarged spleen or splenic 
rupture. 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. 
 
Leukocytosis 
White blood cell counts of 100 x 109/L or greater have been observed in less than 5% of patients 
receiving filgrastim at doses above 0.3 MIU/kg/day (3 µg/kg/day). No undesirable effects directly 
attributable to this degree of leukocytosis have been reported. However, in view of the potential risks 
associated with severe leukocytosis, a white blood cell count should be performed at regular intervals 
during filgrastim therapy. If leukocyte counts exceed 50 x 109/L after the expected nadir, filgrastim 
should be discontinued immediately. However, during the period of administration of filgrastim for 
PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte 
counts rise to > 70 x 109/L. 
 
Risks associated with increased doses of chemotherapy 
Special caution should be used when treating patients with high dose chemotherapy because improved 
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may 
lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please 
refer to the prescribing information of the specific chemotherapy agents used). 
 
Effect of chemotherapy on erythrocytes and thrombocytes 
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to 
myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy 
(e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and 
anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should 
be taken when administering single or combination chemotherapeutic agents which are known to 
cause severe thrombocytopenia. 
 
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of 
thrombocytopenia following myelosuppressive or myeloablative chemotherapy. 
 
Other special precautions 
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been 
studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil 
counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such 
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration 
by tumour). 
 
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been 
reported occasionally in patients undergoing high dose chemotherapy followed by transplantation. 
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF 
after allogeneic bone marrow transplantation (see section 4.8 and 5.1). 
 
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been 
associated with transient abnormal bone scans. This should be considered when interpreting bone-
imaging results. 
 
Special precautions in patients undergoing PBPC mobilization 
 
Mobilization of PBPC 
There are no prospectively randomised comparisons of the two recommended mobilisation methods 



27 
 

(filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patient 
population. The degree of variation between individual patients and between laboratory assays of 
CD34+ cells mean that direct comparison between different studies is difficult. It is therefore difficult 
to recommend an optimal method. The choice of mobilisation method should be considered in relation 
to the overall objectives of treatment for an individual patient.  
 
Prior exposure to cytotoxic agents 
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient 
mobilisation of PBPC to achieve the recommended minimum yield (2.0 x 106 CD34+ cells/kg) or 
acceleration of platelet recovery to the same degree. 
 
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may 
adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and 
carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation, 
may reduce progenitor yield. However, the administration of melphalan, carboplatin or carmustine 
(BCNU) together with filgrastim has been shown to be effective for progenitor mobilisation. When 
peripheral blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell 
mobilization procedure early in the treatment course of the patient. Particular attention should be paid 
to the number of progenitors mobilised in such patients before the administration of high-dose 
chemotherapy. If yields are inadequate, as measured by the criteria above, alternative forms of 
treatment not requiring progenitor support should be considered. 
 
Assessment of progenitor cell yields 
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular 
attention should be paid to the method of quantitation. The results of flow cytometric analysis of 
CD34+ cell numbers vary depending on the precise methodology used and therefore, recommendations 
of numbers based on studies in other laboratories need to be interpreted with caution. 
 
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of 
platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship. 
 
The recommendation of a minimum yield of ≥ 2.0 x 106 CD34+ cells/kg is based on published 
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield 
appear to correlate with more rapid recovery; those below with slower recovery. 
 
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilization 
 
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. Particular attention should be paid to haematological values 
and infectious diseases. The safety and efficacy of filgrastim has not been assessed in normal donors 
less than 16 years or greater than 60 years of age.  
 
Thrombocytopenia 
Thrombocytopenia has been reported very commonly in patients receiving filgrastim .Platelet counts 
should therefore be monitored closely.  
 
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 are < 75 x 109/L.  
 
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects 
in haemostasis. Filgrastim administration should be discontinued or its dosage should be reduced if the 



28 
 

leukocyte counts rise to > 70 x 109/L. Donors who receive G-CSFs for PBPC mobilisation should be 
monitored until haematological indices return to normal.  
 
Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The 
significance of these changes is unknown. Nevertheless, a risk of promotion of a malignant myeloid 
clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and 
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety. 
 
Common but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture 
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of 
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical 
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or 
patients reporting left upper abdominal pain or shoulder tip pain.  
 
In normal donors, dyspnoea has been reported commonly and other pulmonary adverse events 
(haemoptysis, pulmonary haemorrhage, lung infiltrates, and hypoxia) have been reported 
uncommonly. In case of suspected or confirmed pulmonary adverse events, discontinuation of 
treatment with filgrastim should be considered and appropriate medical care given.  
 
Special precautions in recipients of allogeneic PBPC mobilised with filgrastim 
 
Current data indicate that immunological interactions between the allogeneic PBPC graft and the 
recipient may be associated with an increased risk of acute and chronic GvHD when compared with 
bone marrow transplantation. 
 
Special precautions in SCN patients 
 
Blood cell counts 
Thrombocytopenia has been reported commonly in patients receiving filgrastim. Platelet counts should 
be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should 
be given to intermittent cessation or decreasing the dose of filgrastim in patients who develop 
thrombocytopenia, i.e. platelets consistently < 100,000/mm3. 
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, 
which require close monitoring of cell counts. 
 
Transformation to leukaemia or myelodysplastic syndrome 
Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic 
disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell 
counts with differential and platelet counts and an evaluation of bone marrow morphology and 
karyotype should be performed prior to treatment. 
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in 
clinical trial patients with SCN treated with filgrastim. This observation has only been made in 
patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease 
and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had 
normal cytogenetic evaluations at baseline was subsequently found to have abnormalities, including 
monosomy 7, on routine repeat evaluation. If patients with SCN develop abnormal cytogenetics, the 
risks and benefits of continuing filgrastim should be carefully weighed; filgrastim should be 
discontinued if MDS or leukaemia occurs. 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. 
 
Cases of splenomegaly have been reported very commonly and cases of splenic rupture have been 
reported commonly following administration of filgrastim. Individuals receiving filgrastim who report 



29 
 

left upper abdominal and/ or shoulder tip pain should be evaluated for an enlarged spleen or splenic 
rupture. 
 
Splenomegaly   is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of patients in 
studies were documented as having palpable splenomegaly. Increases in volume, measured 
radiographically occurred early during filgrastim therapy and tended to plateau later in treatment. Dose 
reductions were noted to slow or stop the progression of splenic enlargement and in 3% of patients a 
splenectomy was required. Spleen size should be evaluated regularly. Abdominal palpation should be 
sufficient to detect abnormal increases in splenic volume. 
 
Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis 
should be performed to monitor this event. 
 
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been 
established. 
 
Special precautions in patients with HIV infection 
Cases of splenomegaly have been reported  commonly following administration of filgrastim. 
Individuals receiving filgrastim who report left upper abdominal and/ or shoulder tip pain should be 
evaluated for an enlarged spleen or splenic rupture. 
 
Blood cell counts 
ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Some 
patients may respond very rapidly and with a considerable increase in neutrophil count to the initial 
dose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of 
filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice 
weekly for the first two weeks and subsequently once per week or once every other week during 
maintenance therapy. During intermittent dosing with 30 MU (300 microgram)/day of filgrastim, there 
can be wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or 
nadir ANC, it is recommended that blood samples are taken for ANC measurement immediately prior 
to any scheduled dosing with filgrastim. 
 
Risk associated with increased doses of myelosuppressive 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. 
 
Special precautions in sickle cell trait and sickle cell disease 
 
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with 
sickle cell trait or sickle cell disease. Physicians should exercise caution when considering the use of 
filgrastim in patients with sickle cell trait or sickle cell disease and only after careful evaluation of the 
potential risks and benefits. 
 
All patients 
 
Accofil contains sorbitol (E420) as an excipient at a concentration of 50 mg/ml. Patients with rare 
hereditary problems of fructose intolerance should not use this medicinal product. 



30 
 

 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxic 
chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing 
myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended 
in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small 
number of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severity 
of neutropenia may be exacerbated. 
 
Possible interactions with other haematopoietic growth factors and cytokines have not yet been 
investigated in clinical trials. 
 
Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. 
Although this interaction has not been formally investigated, there is no evidence that such an 
interaction is harmful. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited 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 or its metabolites are excreted in human milk. A risk to the breast-
feeding child cannot be excluded. A decision must be made whether to discontinue breastfeeding 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 
 
Accofil may have a minor influence on the ability to drive and use machines.  
 
Dizziness may occur following the administration of Accofil (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 



31 
 

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. 
 
Tabulated list 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.  
 
The assessment of undesirable effects is based on the following frequency data:  
 
Very common: ≥ 1/10  
Common: ≥ 1/100 to < 1/10  
Uncommon: ≥ 1/1,000 to < 1/100  
Rare: ≥ 1/10,000 to < 1/1,000  
Very rare: < 1/10,000  
 
Not known: cannot be estimated from the available data. 
 
MedDRA 
system 
organ class 

Adverse reactions 
Very common  Common  Uncommon  Rare  Ver

y 
rare  
 

Not 
know
n 

Infections 
and 
infestations 

 Sepsis 
Bronchitis 
Upper 
respiratory 
tract infection 
Urinary tract 
infection 

  - - 

Blood and 
lymphatic 
system 
disorders 

Thrombocytope
nia 
Anaemiae 

Splenomegalya 
Haemoglobin 
decreasede 

Leukocytosisa Splenic rupturea 
Sickle cell 
anaemia 
with crisis 

- - 

Immune 
system 
disorders 

  Graft versus 
Host Diseaseb 
Drug 
hypersensitivit
ya 
Hypersensitivi
ty 

Anaphylactic 
reaction 

- - 

Metabolism 
and 
nutrition 
disorders 

 Decreased 
Appetitee 
Blood lactate 
dehydrogenase 
increased 

Hyperuricaemi
a 
Blood uric 
acid 
increased 

Blood glucose 
decreased 
Pseudogouta 
(Chondrocalcino
sis 
Pyrophosphate) 
Fluid volume 

- - 



32 
 

MedDRA 
system 
organ class 

Adverse reactions 
Very common  Common  Uncommon  Rare  Ver

y 
rare  
 

Not 
know
n 

disturbances 
Psychiatric 
disorders 

 Insomnia   - - 

Nervous 
system 
disorders 

Headachea Dizziness, 
Hypoaesthesia
, 
Paraesthesia 

  - - 

Vascular 
disorders 

 Hypotension 
Hypertension 

Veno-
occlusive 
diseased 

Capillary leak 
syndromea 
Aortitis 

- - 

Respiratory
, thoracic 
and 
mediastinal 
disorders 

 Haemoptysis 
Dyspnoea 
Cougha 
Oropharyngeal 
paina,e 
Epistaxis 

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

 - - 

Gastrointes
tinal 
disorders 

Diarrhoeaa,e  
Vomitinga,e  
Nauseaa 

Constipatione 
Oral pain 

  - - 

Hepatobilia
ry disorders 

 Blood alkaline 
phosphatase 
increased 
Hepatomegaly 

Gamma-
glutamyl 
transferase 
increased  
Aspartate 
aminotransfera
se 
increased 

 - - 

Skin and 
subcutaneo
us tissue 
disorders 

Alopeciaa 
 

Rasha  
Erythema 

Rash 
maculopapular 

Sweets 
syndrome (acute 
febrile 
neutrophilic 
dermatosis) 
 Cutaneous 
vasculitisa 

- - 

Musculoske
letal and 
connective 
tissue 
disorders 

Musculoskeletal 
painc 

Muscle 
spasms 

Osteoporosis Bone density 
decreased 
Exacerbation of 
rheumatoid 
arthritis 

- - 

Renal and 
urinary 
disorders 

 Dysuria 
Haematuria 

Proteinuria Urine 
abnormality 

- - 



33 
 

MedDRA 
system 
organ class 

Adverse reactions 
Very common  Common  Uncommon  Rare  Ver

y 
rare  
 

Not 
know
n 

Glomerulonephr
itis 

General 
disorders 
and 
administrat
ion site 
conditions 

Fatiguea  
Mucosal 
inflammationa 
Pyrexia 

Chest paina 
Astheniaa  
Paina 
Malaisee 
Oedema 
peripherale 

Injection site 
reaction 

 - - 

Injury, 
poisoning 
and 
procedural 
complicatio
ns 

 Transfusion 
reactione 

  - - 

 
a See section 4.8, Description of selected adverse reactions  
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow 
transplantation (see section 4.8, Description of selected adverse reactions)  
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, 
musculoskeletal chest pain, neck pain  
d Cases were observed in the post-marketing setting with filgrastim 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 
 
Description of selected adverse reactions 
 
GvHD 
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone 
marrow transplantation (see sections 4.4 and 5.1). 
 
Capillary leak syndrome 
Cases of capillary leak syndrome have been reported in the post marketing setting 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). 
 
In randomised, placebo-controlled clinical studies, filgrastim did not increase the incidence of 
undesirable effects associated with cytotoxic chemotherapy. In those clinical trials, undesirable effects 
reported with equal frequency in cancer patients treated with filgrastim/chemotherapy and 
placebo/chemotherapy included nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, 
headache, cough, skin rash, chest pain, generalised weakness, sore throat, constipation and pain. 
 
In the post-marketing setting cutaneous vasculitis has been reported in patients treated with filgrastim. 
The mechanism of vasculitis in patients receiving filgrastim is unknown. The frequency is estimated 
as uncommon from clinical trial data.  
 
Sweets syndrome 
Cases of Sweets syndrome (acute febrile dermatosis) have been reported in the post-marketing setting. 
The frequency is estimated as uncommon from clinical trial data.  
 
Pulmonary adverse events 



34 
 

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). 
 
Hypersensitivity 
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and 
hypotension occurred on initial or subsequent treatment in clinical studies and in post-marketing 
experience. Overall, reports were more common after intravenous administration. In some cases, 
symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be 
permanently discontinued in patients who experience a serious allergic reaction.  
 
In the post-marketing setting, isolated cases of sickle cell crises have been reported in patients with 
sickle cell disease (see section 4.4). The frequency is estimated as uncommon from clinical trial data. 
 
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. 
 
Pseudogout (chondrocalcinosis pyrophosphate) 
Pseudogout has been reported in cancer patients treated with filgrastim, and the frequency is estimated 
as uncommon from clinical trial data. 
 
Leukocytosis 
Leukocytosis (WBC > 50 x 109/L) was observed in 41% of donors and transient thrombocytopenia 
(platelets < 100 x 109/L) following filgrastim treatment and leukapheresis was observed in 35% of 
donors.  
 
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. 
 
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 are insufficient data to evaluate Accofil use in geriatric subjects for other approved Accofil 
indications.  
 
Paediatric SCN patients 
Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe 
chronic neutropenia receiving chronic treatment with filgrastim.  
  
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 



35 
 

professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The effects of Accofil overdose have not been established. Discontinuation of filgrastim therapy 
usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal 
levels in 1 to 7 days. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: immunostimulants, colony stimulating factors, ATC code: L03AA02 
Accofil is a biosimilar medicinal product. Detailed information is available on the website of the 
European Medicines Agency http://www.ema.europa.eu.  
 
Pharmacodynamic effects 
 
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils 
from the bone marrow. Accofil containing r-metHuG-CSF (filgrastim) causes marked increases in 
peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some SCN 
patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and 
basophils relative to baseline; some of these patients may present with eosinophilia or basophilia 
already prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. 
Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by 
tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating 
neutrophil counts decrease by 50% within 1 to 2 days, and to normal levels within 1 to 7 days.  
 
Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the 
incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim 
significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after 
induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone 
marrow transplantation. The incidence of fever and documented infections were not reduced in either 
setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed 
by bone marrow transplantation.  
 
Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into 
peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic 
therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs 
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.  
 

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


36 
 

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

Publication  Period of 
Study  

N  Acute Grade          
II - IV GvHD  

Chronic 
GvHD  

TRM  

Meta-Analysis   
(2003)  

1986 - 
2001

a 
 

1198  1.08 
(0.87, 1.33)  

1.02 
(0.82, 1.26)  

0.70 
(0.38, 1.31)  

European Retrospective  
Study (2004)  

1992 - 
2002

b 
 

1789  1.33 
    (1.08, 1.64)  

1.29 
(1.02, 1.61)  

1.73 
(1.30, 2.32)  

International 
Retrospective  
Study (2006)  

1995 - 
2000

b 
 

2110  1.11 
  (0.86, 1.42)  

1.10 
(0.86, 1.39)  

1.26 
(0.95, 1.67)  

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

b
Analysis includes patients receiving BM transplant during this period  

 
Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC 
transplantation  
 
In normal donors, a 10 micrograms/kg/day dose administered subcutaneously for 4 - 5 consecutive 
days allows a collection of ≥ 4 x 106 

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

donors after two leukaphereses.  
 
Use of filgrastim in adults with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a 
sustained increase in ANCs in peripheral blood and a reduction of infection and related events.  
 
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled 
dosing of antiviral and/or other myelosuppressive treatments. There is no evidence that patients with 
HIV infection treated with filgrastim show an increase in HIV replication. 
 
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on 
human endothelial cells. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following subcutaneous administration of recommended doses, serum concentrations were maintained 
above10 ng/ml for 8 - 16 hours.  
 
Distribution  
 
The volume of distribution in blood is approximately 150 ml/kg.  
 
Elimination  
 
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous 
or 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 Accofil over a period 
of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no 
evidence of drug accumulation and comparable half-lives.  
 
Linearity 
 
There is a positive linear correlation between the dose and the serum concentration of filgrastim, 
whether administered intravenously or subcutaneously. Following subcutaneous administration of 
recommended doses , serum concentrations were maintained above 10ng/ml for 8 to 16 hours. The 
volume of distribution in blood is approximately 150ml/kg. 



37 
 

 
5.3 Preclinical safety data 
 
Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed 
changes attributable to the expected pharmacological actions including increases in leukocytes, 
myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These 
changes all reversed after discontinuation of treatment. 
Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous (80 
µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally 
toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size 
and fetal weight were observed. 
Based on reported data for another filgrastim product similar to Accofil, comparable findings plus 
increased fetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which 
corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients 
treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level for embryo-fetal 
toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of approximately 
3-5 times the exposures observed in patients treated with the clinical dose. 
In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of 
rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external 
differentiation and growth retardation (≥20 µg/kg/day) and slightly reduced survival rate (100 
µg/kg/day). 
Filgrastim had no observed effect on the fertility of male or female rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Acetic acid glacial 
Sodium hydroxide 
Sorbitol (E420)  
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Accofil must not be diluted with sodium chloride solutions.  
 
Diluted filgrastim may be adsorbed to glass and plastic materials. 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.  
 
6.3 Shelf life 
 
3 years. 
 
Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 
24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless 
dilution has taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). Do not freeze.  
 



38 
 

Accidental one-time exposure to freezing temperatures does not adversely affect the stability of Accofil. 
If exposure has been greater than 24 hours or frozen more than once then Accofil should NOT be 
used. 
 
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from 
the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 
days. At the end of this period, the product should not be put back in the refrigerator and should be 
disposed of. 
 
Keep the syringe in the outer carton in order to protect from light. 
 
For storage conditions of the diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass pre-filled syringe with a permanently attached stainless steel needle in the tip and 1/40 
printed markings for graduations from 0.1 mL to 1 mL on the barrel. The needle cover of the pre-filled 
syringe contains dry natural rubber (see section 4.4). Each pre-filled syringe contains 0.5 ml solution. 
 
Each pack contains one, three, five, seven or ten pre-filled syringes, with or without a needle safety 
guard, and alcohol swabs. The packs without blister are for syringes without needle safety guard. The 
blister packs are for individual syringes with prefixed needle safety guard. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
If required, Accofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 
(2 µg) per ml is not recommended at any time. 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used. Do not shake.  
 
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per ml, human 
serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final 
injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 µg) should be given with 0.2 
ml of 200 mg/ml (20%) human albumin solution added. 
 
Accofil contains no preservative. In view of the possible risk of microbial contamination, Accofil  
pre-filled syringes are for single use only. 
 
When diluted in 5% glucose, Accofil is compatible with glass and a variety of plastics including PVC, 
polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene. 
 
Using the pre-filled syringe with a needle safety guard  
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 
plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger.  
 
Using the pre-filled syringe without a needle safety guard  
 
Administer the dose as per standard protocol. 
 



39 
 

Disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/003 
EU/1/14/946/004 
EU/1/14/946/011 
EU/1/14/946/012 
EU/1/14/946/013 
EU/1/14/946/014 
EU/1/14/946/015 
EU/1/14/946/016 
EU/1/14/946/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 18.09.2014 
Date of latest renewal: 12th June 2019 
 
 
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 
 

 
   



40 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

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

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



41 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) of the biological active substance(s)  
Intas Pharmaceuticals Ltd. 
Plot no: 423/P/A 
Sarkhej Bavla Highway 
Village Moraiya; Taluka Sanand, 
Ahmedabad – 382213 Gujarat 
India 
 
Name and address of the manufacturer(s) responsible for batch release 
Accord Healthcare Ltd. 
Sage House 
319 Pinner Road 
North Harrow 
Middlesex, HA1 4HF 
United Kingdom 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland 
 
Accord Healthcare B.V.,  
Winthontlaan 200,  
3526 KV Utrecht,  
The Netherlands 
 
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 PSURs 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: 
 



42 
 

• At the request of the European Medicines Agency; 
 
• Whenever the risk management system is modified, especially as the result of new information being 
received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached.  
 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

  



43 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



44 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

 
A. LABELLING 



45 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 30 MU/0.5 ml solution for injection/infusion 
filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each syringe in 0.5 ml contains 30 MU of filgrastim (0.6 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injection. See leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 pre-filled syringe (0.5 ml) + 1 alcohol swab 
“5 pre-filled syringes (0.5 ml) + 5 alcohol swabs” 
“3 pre-filled syringe (0.5 ml) + 3 alcohol swabs” 
“10 pre-filled syringe (0.5 ml) + 10 alcohol swabs” 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
For single use only. 
Subcutaneous or intravenous use. 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 



46 
 

Keep the syringe in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/001 - 1 prefilled syringe 
EU/1/14/946/002 - 5 prefilled syringes 
EU/1/14/946/006 - 3 prefilled syringe 
EU/1/14/946/009 - 10 prefilled syringe 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Accofil 30 MU/0.5 ml 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:   
SN:   
NN:  
 
 
 
 



47 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer Carton – Pre-filled syringe with a needle safety guard in blister pack 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 30 MU/0.5 ml solution for injection/infusion 
filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each syringe in 0.5 ml contains 30 MU of filgrastim (0.6 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injection. See leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 pre-filled syringe (0.5 ml) + 1 alcohol swab   
“3 pre-filled syringe (0.5 ml) + 3 alcohol swabs”   
“5 pre-filled syringes (0.5 ml) + 5 alcohol swabs”   
“10 pre-filled syringe (0.5 ml) + 10 alcohol swabs”   
“7 pre-filled syringe (0.5 ml) + 7 alcohol swabs” 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
For single use only. 
Subcutaneous or intravenous use. 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 



48 
 

Keep the syringe in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/005 – 1 prefilled syringe with a needle safety guard 
EU/1/14/946/008 – 5 prefilled syringes with a needle safety guard 
EU/1/14/946/007 – 3 prefilled syringe with a needle safety guard 
EU/1/14/946/010 – 10 prefilled syringe with a needle safety guard 
EU/1/14/946/017 – 7 prefilled syringe with a needle safety guard 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Accofil 30 MU/0.5 ml 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:   
SN:   
NN: 
 
 
 



49 
 

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



50 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 48 MU/0.5 ml solution for injection/infusion 
filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each syringe in 0.5 ml contains 48 MU of filgrastim (0.96 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injection. See leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 pre-filled syringe (0.5 ml) + 1 alcohol swab 
“5 pre-filled syringes (0.5 ml) + 5 alcohol swabs” 
“3 pre-filled syringe (0.5 ml) + 3 alcohol swabs” 
“10 pre-filled syringe (0.5 ml) + 10 alcohol swabs” 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
For single use only. 
Subcutaneous or intravenous use. 
Do not shake. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 



51 
 

Keep the syringe in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/003 - 1 prefilled syringe 
EU/1/14/946/004 - 5 prefilled syringes 
EU/1/14/946/012 - 3 prefilled syringe 
EU/1/14/946/015 - 10 prefilled syringe 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Accofil 48 MU/0.5 ml 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:   
NN: 
 
 
 
 



52 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer Carton – Pre-filled syringe with a needle safety guard in blister pack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Accofil 48 MU/0.5 ml solution for injection/infusion 
filgrastim 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each syringe in 0.5 ml contains 48 MU of filgrastim (0.96 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80, and water for injection. See leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 pre-filled syringe (0.5 ml) + 1 alcohol swab   
“3 pre-filled syringe (0.5 ml) + 3 alcohol swabs” 
“5 pre-filled syringes (0.5 ml) + 5 alcohol swabs”   
“10 pre-filled syringe (0.5 ml) + 10 alcohol swabs” 
“7 pre-filled syringe (0.5 ml) + 7 alcohol swabs” 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
For single use only. 
Subcutaneous or intravenous use. 
Do not shake. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



53 
 

Store in a refrigerator. Do not freeze. 
Keep the syringe in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/946/011 – 1 prefilled syringe with a needle safety guard 
EU/1/14/946/014 – 5 prefilled syringes with a needle safety guard 
EU/1/14/946/013 – 3 prefilled syringe with a needle safety guard 
EU/1/14/946/016 – 10 prefilled syringe with a needle safety guard 
EU/1/14/946/018 – 7 prefilled syringe with a needle safety guard 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Accofil 48 MU/0.5 ml 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 



54 
 

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



55 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



56 
 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Accofil 30 MU/0.5 ml (0.6 mg/ml) solution for injection or infusion in pre-filled syringe 
filgrastim 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, nurse or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even 
if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. See section 4. 
 
In this leaflet 
 
1. What Accofil is and what it is used for 
2. What you need to know before you use Accofil 
3. How to use Accofil 
4. Possible side effects 
5.      How to store Accofil 
6.      Contents of the pack and other information 
 
 
1. What Accofil is and what it is used for 
 
What Accofil is 
 
Accofil contains the active ingredient filgrastim. Filgrastim is a protein produced in bacteria called 
Escherichia coli by recombinant DNA technology. It belongs to a group of proteins called cytokines 
and is very similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by 
your own body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to 
produce more white blood cells that help fight infection.  
 
What Accofil is used for 
 
Your doctor has prescribed Accofil for you to help your body make more white blood cells. Your 
doctor will tell you why you are being treated with Accofil. Accofil is useful in several different 
conditions which are: 
 
-  chemotherapy  
-  bone marrow transplantation 
-  severe chronic neutropenia (low number of a type of white blood cells) 
-  neutropenia (low number of a type of white blood cells) in patients with HIV infection  
- peripheral blood stem cell mobilisation (to stimulate stem cells to enter the blood stream to be 
collected and used in bone marrow transplantation). 
 
 
2. What you need to know before you use Accofil 
 
Do not use Accofil 
 
- If you are allergic (hypersensitive) to filgrastim or any of the other ingredients of this medicine 
(listed in section 6). 
 
Warnings and precautions 



57 
 

 
Talk to your doctor, pharmacist or nurse before using Accofil: 
 
Please tell your doctor before starting treatment if you have: 
• Sickle cell anaemia, accofil may cause sickle cell crisis. 
• Osteoporosis (bone disease)  
 
Please tell your doctor immediately during treatment with Accofil, if you: 
• Get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder 
(these may be symptoms of enlarge spleen (splenomegaly) or possibly rupture of spleen). 
 
• Notice unusual bleeding or bruising that may be (these may be symptoms of a decrease in blood 
platelets (thrombocytopenia), with a reduced ability of your blood to clot. 
 
• Have sudden signs of allergy such as rash, itching or hives of skin, swelling of the face, lips, tongue 
or other parts of the body, shortness of breath, wheezing or trouble breathing as these could be a signs 
of severe allergic reaction.   

 
• Experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you 
notice you urinate less than usual (glomerulonephritis). 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may 
cause an allergic reaction. 
 
Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) 
has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, 
abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you 
experience these symptoms. 
 
Loss of response to filgrastim 
If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 
doctor will investigate the reasons why including whether you have developed antibodies which 
neutralise filgrastim’s activity 
Your doctor may want to monitor you closely, see section 4 of the package leaflet. 
If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the 
blood (leukaemia, myelodysplastic syndrome (MDS)) You should talk to your doctor about your risks 
of developing cancers of the blood and what testing should be done. If you develop or are likely to 
develop cancers of the blood, you should not use Accofil, unless instructed by your doctor. 
If you are a stem cell donor, you must be aged between16 and 60 years. 
 
Take special care with other products that stimulate white blood cells 
Accofil 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 Accofil 
 
You should not receive Accofil in the 24 hours before and the 24 hours after receiving chemotherapy. 
 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Pregnancy and breast-feeding 
 
Accofil has not been tested in pregnant women. 
 
It is important to tell your doctor if you:  

• are pregnant or breast-feeding; 



58 
 

• think you may be pregnant; or 
• are planning to have a baby. 

 
It is unknown whether filgrastim passes over into the breast milk. Therefore, your doctor may decide 
that you should not use this medicine if you are breast-feeding. 
 
Driving and using machines 
 
Accofil may have a minor influence on your ability to drive and use machines. This medicine may 
cause dizziness. It is advisable to wait and see how you feel after taking Accofil and before driving or 
operating machinery. 
 
Accofil contains sorbitol and sodium 
 
This medicine contains sorbitol. If you have been told by your doctor that you have an intolerance to 
some sugars (fructose), contact your doctor before taking this medicine.  
 
This medicine also contains sodium less than 1mmol sodium (0.035 mg) per dose, i.e. essentially 
‘sodium-free’.  
 
 
3. How to use Accofil 
 
Always use Accofil exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
The amount of Accofil you need will depend on the condition you are taking Accofil for and on your 
bodyweight. 
 
Dosage 
 
Accofil and neutropenia (low number of a type of white blood cells) associated with chemotherapy  
 
The usual dose is 0.5 million units (5 micrograms) per kilogram of bodyweight each day. For example, 
if you weigh 60 kilograms your daily dose will be 30 million units (300 micrograms). Your treatment 
with Accofil will usually last for about 14 days. In some disease types, however, longer treatment 
lasting up to about one month may be required. 
 
Accofil and bone marrow transplantation  
 
The usual starting dose is 1 million units (10 micrograms) per kilogram of bodyweight each day given 
as an infusion. For example, if you weigh 60 kilograms your daily dose will be 60 million units (600 
micrograms). You will normally receive your first dose of Accofil at least 24 hours after your 
chemotherapy and at least 24 hours after receiving your bone marrow transplant. Your doctor may 
then test your blood to see how well the treatment is working and how long it should last. 
 
Accofil and severe chronic neutropenia (low number of a type of white blood cells)  
 
The usual starting dose is between 0.5 million units  (5 micrograms) and 1.2 million units (12 
micrograms) per kilogram bodyweight each day in a single or divided dose. Your doctor may then test 
your blood to see how well your treatment with Accofil is working and to find the dose that is best for 
you. Long-term treatment with Accofil is required for reduction in neutropenia. 
 
Accofil and neutropenia (low number of a type of white blood cells) in patients with HIV infection  
 
The usual starting dose is between 0.1 million units (1 micrograms) and 0.4 million units (4 
micrograms) per kilogram bodyweight each day. Your doctor may test your blood at regular intervals 



59 
 

to see how well the Accofil treatment is working. Once the number of white cells in your blood has 
returned to normal it may be possible to reduce the dose frequency to less than once per day. Long 
term treatment with Accofil may be required to maintain a normal number of white cells in your 
blood.  
 
Accofil and peripheral blood stem cell transplantation (stem cells collected from the blood to use in 
bone marrow transplantation) 
 
If you are donating stem cells for yourself, the usual dose is 0.5 million units (5 micrograms) to 1 
million units (10 micrograms) per kilogram bodyweight each day. Accofil treatment will last for up to 
2 weeks. Your doctor will monitor your blood to determine the best time to collect the stem cells.  
If you are acting as a stem cell donor for another person, the usual dose is 1 million units (10 
micrograms) per kilogram bodyweight each day. Accofil treatment will last for 4 to 5 days. Your 
doctor will perform regular blood tests to determine the best time to collect the stem cells. 
 
How Accofil is given 
 
This medicine is given by injection, either through an intravenous (IV) infusion (drip) or by a 
subcutaneous (SC) injection into the tissue just under the skin.  
 
If you are receiving this medicine by subcutaneous injection, your doctor may suggest that you learn 
how to give yourself the injections. Your doctor or nurse will give you instructions on how to do this 
(see information below on instructions for injecting Accofil). Do not attempt to self-administer 
without this training. Some of the information you require is given at the end of this leaflet, but proper 
treatment of your disease requires close and constant co-operation with your doctor. 
 
Information for injecting yourself  
This section contains information on how to give yourself an injection of Accofil. 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 Accofil 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 Accofil; 
• alcohol swab or similar. 
 
What should I do before I give myself a subcutaneous injection of Accofil?  
Ensure the needle cover remains on the syringe until just before you are ready to inject. 
a. Take your Accofil pre-filled syringe out of the refrigerator.  
b. 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 or if it has been kept outside of the refrigerator for more than 15 days 
or has otherwise expired.  
c. Check the appearance of Accofil. It must be a clear and colourless liquid. If there are particles in 
it, you must not use it.  
d. 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 Accofil 
in any other way (for example, do not warm it in a microwave or in hot water).  
e. Wash your hands thoroughly.  
f. Find a comfortable, well-lit place and put everything you need where you can reach them (the 
Accofil pre-filled syringe and alcohol swab). 
 
How do I prepare my Accofil injection?  



60 
 

Before you inject Accofil 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. . You do not have to remove the air 
bubble before injecting. Injecting the solution with the air bubble is harmless. 
3. The syringe may contain more liquid than you need. Use the scale on the syringe barrel as 
follows to set the correct dose of Accofil that your doctor prescribed. Eject unnecessary liquid by 
pushing the plunger up to the number (mL) on the syringe that matches the prescribed dose.  
4. Check again to make sure the correct dose of Accofil 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). 
 



61 
 

3 

 
 
If someone else is injecting you, they can also use the back of your arms (see picture 4) 
 

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?  
a. Disinfect the injection site by using an alcohol swab and pinch the skin between your thumb and 
forefinger, without squeezing it (see picture 5).  
 



62 
 

5 

 
 
Pre-filled syringe without needle safety guard 
 
b. Put the needle fully into the skin as shown by your nurse or doctor (see picture 6).  
c. 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.  
d. Always keeping your skin pinched, depress the plunger slowly and evenly until the entire dose 
has been given and the plunger cannot be depressed any further. Do not release the pressure on the 
plunger! 
e. Inject only the dose your doctor has told you. 
f. After injecting the liquid, remove the needle while maintaining pressure on the plunger and then let 
go of your skin. 
g. Put the used syringe in the disposal container. Use each syringe only for one injection. 
 

6 

 
 
Pre-filled syringe with needle safety guard 
 
h. Put the needle fully into the skin as shown by your nurse or doctor (see picture 7).  
i. 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.  
j. Inject only the dose your doctor has told you following the instructions below. 
k. Always keeping your skin pinched, depress the plunger slowly and evenly while grasping the 
finger flange until the entire dose has been given and the plunger cannot be depressed any further. Do 
not release the pressure on the plunger!  
l. After injecting the liquid, remove the needle while keeping the syringe at the same angle and 
maintaining pressure on the plunger, then let go of your skin. The protective sleeve will automatically 
cover the needle and an audible “click” will be heard to confirm shield activation (see picture 8). The 
needle guard will not activate unless the entire dose has been given. 
 



63 
 

 

7 

 
  

 

8 

 
 
 
Remember  
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice.  
 
Disposing of used syringes  
• The needle safety guard prevents needle stick injuries after use, so no special precautions for 
disposal are required. Dispose of the syringe as instructed by your doctor, nurse or pharmacist. 
 
If you use more Accofil than you should 
 
If you use more Accofil than you should, contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Accofil 
 
Do not take a double dose to make up for a forgotten injection. Contact your doctor to discuss when 
you should inject the next dose. 
 



64 
 

If you stop using Accofil 
 
Your doctor will tell you when to stop using Accofil. It is quite normal to have a number of courses of 
treatment with Accofil.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately during treatment: 
 
• if you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face, lips, 
mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea). Hypersensitivity is common 
in patients with cancer; 
• if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of Acute 
Respiratory Distress Syndrome (ARDS). ARDS is uncommon in patients with cancer;  
• if you get left upper belly (abdonimal) pain, pain below the left rib cage or pain at the tip of your 
shoulder since this may relate to a problem with your spleen (enlargement of the spleen 
(splenomegaly) or rupture of the spleen)..  
• if you are being treated for severe chronic neutropenia and you have blood in your urine 
(haematuria). Your doctor may regularly test your urine if you experience this side effect or if protein 
is found in your urine (proteinuria). 
• If you have any of the following or a combination of the following side effects: swelling or 
puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal 
swelling and feeling of fullness, and a general feeling of tiredness. These symptoms generally develop 
in a rapid fashion.  
 
These could be symptoms of an uncommon condition (may affect up to 1 in 100 people) called 
Capillary Leak Syndrome which causes the blood to leak from the small blood vessels into your body 
and needs urgent medical attention.  
 
• If you have a combination of any of the following symptoms: 
  - fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, 
shortness of breath, extreme pain or discomfort and clammy or sweaty skin. 
 
These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 
severe infection with whole-body inflammatory response which can be life threatening and 
needs urgent medical attention. 
 
if you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients who 
received Accofil. Call your doctor right away if you experience puffiness in your face or ankles, blood 
in your urine or brown-coloured urine or you notice you urinate less than usual 
 
A very frequent side effect of Accofil use is pain in your muscles or bones (musculoskeletal pain), 
which can be helped by taking standard pain relief medicines (analgesics). In patients undergoing a 
stem cell or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of 
the donor cells against the patient receiving the transplant; signs and symptoms include rash on the 
palms of your hands and soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your 
eyes, lungs, vagina and joints. Very commonly seen in normal stem cells donors is increase in white 
blood cells (leukocytosis) and decrease of platelets which reduces the ability of blood to clot 
(thrombocytopenia), these will be monitored by your doctor. 
 
 



65 
 

 
Very common side effects (seen in more than 1 in 10 people who take Accofil): 
• 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) 
• decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 
• low red blood cell count (anaemia) 
• fever (pyrexia) 
• headache 
• diarrhoea 
 
Common side effects (seen in more than 1 in 100 people taking Accofil):  
• inflammation of the lung (bronchitis) 
• upper respiratory tract infection 
•  urinary tract infection 
•  decreased appetite 
•  trouble sleeping (insomnia) 
•  dizziness 
•  decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 
•  tingling or numbness of the hands or feet (paraesthesia) 
•  low blood pressure (hypotension) 
•  high blood pressure (hypertension) 
•  cough 
•  coughing up blood (haemoptysis) 
•  pain in your mouth and throat (oropharyngeal pain) 
•  nose bleeds (epistaxis) 
•  constipation 
•  oral pain 
•  enlargement of the liver (hepatomegaly) 
•  rash 
•  redness of the skin (erythema) 
•  muscle spasm 
•  pain when passing urine (dysuria) 
•  chest pain 
•  pain 
•  generalised weakness (asthenia) 
•  generally feeling unwell (malaise) 
•  swelling in the hands and feet (oedema peripheral) 
•  increase of certain enzymes in the blood 
•  changes in blood chemistry 
•  transfusion reaction 
 
Uncommon side effects (seen in more than 1 in 1000 people taking Accofil):  
• increase in white blood cells (leukocytosis) 
•  allergic reaction (hypersensitivity) 
•  rejection of transplanted bone marrow (graft versus host disease) 
•  high uric acid levels in the blood, which may cause gout (hyperuricaemia) (Blood uric acid 

increased) 
•  liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 
•  lungs do not function as they should, causing breathlessness (respiratory failure) 
•  swelling and/or fluid in the lungs (pulmonary oedema) 



66 
 

•  inflammation of the lungs (interstitial lung disease) 
•  abnormal x-rays of the lungs (lung infiltration) 
•  bleeding from the lung (pulmonary haemorrhage) 
•  lack of absorption of oxygen in the lung (hypoxia) 
•  bumpy skin rash (rash macuo-papular) 
•  disease which causes bones to become less dense, making them weaker, more brittle and likely 

to break (osteoporosis) 
•  injection site reaction 
 
Rare side effects (seen in more than 1 in 10,000 people taking Accofil): 
• Inflammation of the aorta (the large blood vessel which transports blood from the 
heart to the body), see section 2. 
• 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 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not 
listed in this leaflet. 
 
Reporting of side effects  
 
If you get any side effects, talk to your doctor. 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 Accofil 
 
Keep out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and on the pre-filled 
syringe after EXP. The expiry date refers to the last day of the month. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze. 
 
The syringe can be removed from the refrigerator and left at room temperature (not above 25°C) for a 
single period, that ends within the labelled expiry date, of up to a maximum of 15 days. At the end of 
this period, the product should not be put back in the refrigerator and should be disposed of. 
 
Keep the pre-filled syringe in the carton in order to protect from light. 
 
Do not use Accofil if you notice it is cloudy, or there is discoloration or there are particles in it. 
 
Do not put the cover back on used needles, as you may accidentally prick yourself. Medicines should 
not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of 
medicines no longer required. These measures will help to protect the environment. 
 
 

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


67 
 

6. Contents of the pack and other information 
 
What Accofil contains  
 
- The active substance is filgrastim. Each pre-filled syringe contains 30 MU (300 micrograms) 
filgrastim in 0.5 ml, corresponding to 0.6 mg/ml.  
- The other ingredients are acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80 and water 
for injections. 
 
What Accofil looks like and contents of the pack 
 
Accofil is a clear colourless solution for injection or infusion in a pre-filled syringe marked with 1/40 
printed markings from 0.1 mL to 1 mL on the syringe barrel, with an injection needle. Each pre-filled 
syringe contains 0.5 ml of solution. 
 
Accofil is available in packs containing 1, 3, 5, 7 and 10 pre-filled syringes, with or without prefixed 
needle safety guard and alcohol swabs.   
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
Manufacturer 
Accord Healthcare Limited 
Sage House, 319 Pinner Road 
North Harrow,  
Middlesex, HA1 4HF 
United Kingdom 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland                                                                                                                                 
 
Accord Healthcare B.V.,  
Winthontlaan 200,  
3526 KV Utrecht,  
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

AT / BE / BG / CY / CZ / DE / DK /  
EE / EL / FI / HR / HU / IS / LT /  
LV / LX/ MT / NL / NO / PT /  
PL / RO / SE / SI / SK / UK/ ES 
 Accord Healthcare S.L.U. 
Tel: +34 93 301 00 64 
 
 

FR 
Accord Healthcare France SAS  
+33 3 20 40 17 70 
 
 
 



68 
 

 IT 
Accord Healthcare Limited 
Tel: +39 02 94323700 
 
 
 

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  
 
 
--------------------------------------------------------------------------------------------------------------- 
The following information is intended for medical or healthcare professionals only:  
 
Accofil does not contain any preservative. In view of the possible risk of microbial contamination, 
Accofil syringes are for single use only. 
 
Accidental exposure to freezing temperatures for up to 24 hours does not affect the stability of 
Accofil. If exposure has been greater than 24 hours or frozen more than once then Accofil should NOT 
be used. 
 
In order to improve traceability of granulocyte-colony stimulating factors, the product name (Accofil) 
and batch number of the administered product should be clearly recorded in the patient file 
 
Accofil 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, Accofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 
(2 µg) per ml is not recommended at any time. 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used.  
 
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per ml, human 
serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final 
injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 µg) should be given with 0.2 
ml of 200 mg/ml (20%) human albumin solution added. 
 
When diluted in 5% glucose, Accofil 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. 
 
Using the pre-filled syringe with a needle safety guard  
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 



69 
 

plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger.  
 
Using the pre-filled syringe without a needle safety guard 
 
Administer the dose as per standard protocol. 
 
Disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 



70 
 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Accofil 48 MU/0.5 ml (0.96 mg/ml) solution for injection or infusion in pre-filled syringe 
filgrastim 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, nurse or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even 
if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. See section 4. 
 
In this leaflet 
 
1. What Accofil is and what it is used for 
2. What you need to know before you use Accofil 
3. How to use Accofil 
4. Possible side effects 
5. How to store Accofil 
6. Contents of the pack and other information 
 
 
1. What Accofil is and what it is used for 
 
What Accofil is 
 
Accofil contains the active ingredient filgrastim. Filgrastim is a protein produced in bacteria called 
Escherichia coli by recombinant DNA technology. It belongs to a group of proteins called cytokines 
and is very similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by 
your own body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to 
produce more white blood cells that help fight infection.  
 
What Accofil is used for 
 
Your doctor has prescribed Accofil for you to help your body make more white blood cells. Your 
doctor will tell you why you are being treated with Accofil. Accofil is useful in several different 
conditions which are: 
 
-  chemotherapy  
-  bone marrow transplantation 
-  severe chronic neutropenia (low number of a type of white blood cells) 
-  neutropenia (low number of a type of white blood cells) in patients with HIV infection  
- peripheral blood stem cell mobilisation (to stimulate stem cells to enter the blood stream to be 
collected and used in bone marrow transplantation). 
 
 
2. What you need to know before you use Accofil 
 
Do not use Accofil 
 
- If you are allergic (hypersensitive) to filgrastim or any of the other ingredients of this medicine 
(listed in section 6). 
 
 



71 
 

Warnings and precautions 
 
Talk to your doctor before using Accofil: 
 
Talk to your doctor, pharmacist or nurse before using Accofil: 
 
Please tell your doctor before starting treatment if you have: 
• Sickle cell anaemia, accofil may cause sickle cell crisis. 
• Osteoporosis (bone disease)  
 
Please tell your doctor immediately during treatment with Accofil, if you: 
• Get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder( 
these may be symptoms of enlarge spleen (splenomegaly) or possibly rupture of spleen). 
 
• Notice unusual bleeding or bruising that may be (these may be symptoms of a decrease in blood 
platelets (thrombocytopenia), with a reduced ability of your blood to clot). 
 
• Have sudden signs of allergy such as rash, itching or hives of skin, swelling of the face, lips,tongue 
or other parts of the body, shortness of breath, wheezing or trouble breathing as these could be a signs 
of severe allergic reaction.   
 
• Experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you 

notice you urinate less than usual (glomerulonephritis). 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may 
cause an allergic reaction. 
 
Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) 
has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, 
abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you 
experience these symptoms. 
 
Loss of response to filgrastim 
If you experience a loss of response or failure to maintain a response with filgrastim treatment, your 
doctor will investigate the reasons why including whether you have developed antibodies which 
neutralise filgrastim’s activity 
Your doctor may want to monitor you closely, see section 4 of the package leaflet. 
If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the 
blood (leukaemia, myelodysplastic syndrome (MDS)) You should talk to your doctor about your risks 
of developing cancers of the blood and what testing should be done. If you develop or are likely to 
develop cancers of the blood, you should not use Accofil, unless instructed by your doctor. 
If you are a stem cell donor, you must be aged between16 and 60 years. 
 
Take special care with other products that stimulate white blood cells 
Accofil 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 Accofil 
 
You should not receive Accofil in the 24 hours before and the 24 hours after receiving chemotherapy. 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Pregnancy and breast-feeding 
 
Accofil has not been tested in pregnant women. 
 



72 
 

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. 

  
It is unknown whether filgrastim passes over into the breast milk. Therefore, your doctor may decide 
that you should not use this medicine if you are breast-feeding. 
 
Driving and using machines 
 
Accofil may have a minor influence on  your ability to drive and use machines. This medicine may 
cause dizziness. It is advisable to wait and see how you feel after taking Accofil and before driving or 
operating machinery.  
 
Accofil contains sorbitol and sodium 
 
This medicine contains sorbitol. If you have been told by your doctor that you have an intolerance to 
some sugars (fructose), contact your doctor before taking this medicine.  
 
This medicine also contains sodium less than 1mmol sodium (0.035 mg) per dose, i.e. essentially 
‘sodium-free’.  
 
 
3. How to use Accofil 
 
Always use Accofil exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
The amount of Accofil you need will depend on the condition you are taking Accofil for and on your 
bodyweight. 
 
Dosage 
 
Accofil and neutropenia (low number of a type of white blood cells) associated with chemotherapy  
 
The usual dose is 0.5 million units (5 micrograms) per kilogram of bodyweight each day. For example, 
if you weigh 60 kilograms your daily dose will be 30 million units (300 micrograms). Your treatment 
with Accofil will usually last for about 14 days. In some disease types, however, longer treatment 
lasting up to about one month may be required. 
 
Accofil and bone marrow transplantation  
 
The usual starting dose is 1 million units (10 micrograms) per kilogram of bodyweight each day given 
as an infusion. For example, if you weigh 60 kilograms your daily dose will be 60 million units (600 
micrograms). You will normally receive your first dose of Accofil at least 24 hours after your 
chemotherapy and at least 24 hours after receiving your bone marrow transplant. Your doctor may 
then test your blood to see how well the treatment is working and how long it should last. 
 
Accofil and severe chronic neutropenia (low number of a type of white blood cells)  
 
The usual starting dose is between 0.5 million units  (5 micrograms) and 1.2 million units (12 
micrograms) per kilogram bodyweight each day in a single or divided dose. Your doctor may then test 
your blood to see how well your treatment with Accofil is working and to find the dose that is best for 
you. Long-term treatment with Accofil is required for reduction in neutropenia. 
 
Accofil and neutropenia (low number of a type of white blood cells) in patients with HIV infection  
 



73 
 

The usual starting dose is between 0.1 million units (1 micrograms) and 0.4 million units (4 
micrograms) per kilogram bodyweight each day. Your doctor may test your blood at regular intervals 
to see how well the Accofil treatment is working. Once the number of white cells in your blood has 
returned to normal it may be possible to reduce the dose frequency to less than once per day. Long 
term treatment with Accofil may be required to maintain a normal number of white cells in your 
blood.  
 
Accofil and peripheral blood stem cell transplantation (stem cells collected from the blood to use in 
bone marrow transplantation) 
 
If you are donating stem cells for yourself, the usual dose is 0.5 million units (5 micrograms) to 1 
million units (10 micrograms) per kilogram bodyweight each day. Accofil treatment will last for up to 
2 weeks. Your doctor will monitor your blood to determine the best time to collect the stem cells.  
If you are acting as a stem cell donor for another person, the usual dose is 1 million units (10 
micrograms) per kilogram bodyweight each day. Accofil treatment will last for 4 to 5 days. Your 
doctor will perform regular blood tests to determine the best time to collect the stem cells. 
 
How Accofil is given 
 
This medicine is given by injection, either through an intravenous (IV) infusion (drip) or by a 
subcutaneous (SC) injection into the tissue just under the skin.  
 
If you are receiving this medicine by subcutaneous injection, your doctor may suggest that you learn 
how to give yourself the injections. Your doctor or nurse will give you instructions on how to do this 
(see information below on instructions for injecting Accofil). Do not attempt to self-administer 
without this training. Some of the information you require is given at the end of this leaflet, but proper 
treatment of your disease requires close and constant co-operation with your doctor. 
 
Information for injecting yourself  
This section contains information on how to give yourself an injection of Accofil. 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 Accofil 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 Accofil; 
• alcohol swab or similar. 
 
What should I do before I give myself a subcutaneous injection of Accofil?  
Ensure the needle cover remains on the syringe until just before you are ready to inject. 
a. Take your Accofil pre-filled syringe out of the refrigerator. 
b. 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 or if it has been kept outside of the refrigerator for more than 15 days 
or has otherwise expired. 
c. Check the appearance of Accofil. It must be a clear and colourless liquid. If there are particles in 
it, you must not use it. 
d. 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 Accofil 
in any other way (for example, do not warm it in a microwave or in hot water). 
e. Wash your hands thoroughly. 
f. Find a comfortable, well-lit place and put everything you need where you can reach them (the 
Accofil pre-filled syringe and alcohol swab). 



74 
 

 
How do I prepare my Accofil injection?  
Before you inject Accofil 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. . You do not have to remove the air 
bubble before injecting. Injecting the solution with the air bubble is harmless. 
3. The syringe may contain more liquid than you need. Use the scale on the syringe barrel as 
follows to set the correct dose of Accofil that your doctor prescribed. Eject unnecessary liquid by 
pushing the plunger up to the number (mL) on the syringe that matches the prescribed dose. 
4. Check again to make sure the correct dose of Accofil 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). 
 



75 
 

3 

 
 
If someone else is injecting you, they can also use the back of your arms (see picture 4). 
 

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?  
a. Disinfect the injection site by using an alcohol swab and pinch the skin between your thumb and 
forefinger, without squeezing it (see picture 5).  
 



76 
 

5 

 
 
Pre-filled syringe without needle safety guard 
 
b. Put the needle fully into the skin as shown by your nurse or doctor (see picture 6).  
c. 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.  
d. Always keeping your skin pinched, depress the plunger slowly and evenly until the entire dose 
has been given and the plunger cannot be depressed any further. Do not release the pressure on the 
plunger! 
e. Inject only the dose your doctor has told you. 
f. After injecting the liquid, remove the needle while maintaining pressure on the plunger and then let 
go of your skin. 
g. Put the used syringe in the disposal container. Use each syringe only for one injection. 
 

6 

 
 
Pre-filled syringe with needle safety guard 
 
h. Put the needle fully into the skin as shown by your nurse or doctor (see picture 7).  
i. 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.  
j. Inject only the dose your doctor has told you following the instructions below. 
k. Always keeping your skin pinched, depress the plunger slowly and evenly while grasping the 
finger flange until the entire dose has been given and the plunger cannot be depressed any further. Do 
not release the pressure on the plunger!  
l. After injecting the liquid, remove the needle while keeping the syringe at the same angle and 
maintaining pressure on the plunger, then let go of your skin. The protective sleeve will automatically 
cover the needle and an audible “click” will be heard to confirm shield activation (see picture 8). The 
needle guard will not activate unless the entire dose has been given. 
 



77 
 

 

7 

 
  

 

8 

 
 
 
Remember  
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice.  
 
Disposing of used syringes  
• The needle safety guard prevents needle stick injuries after use, so no special precautions for 
disposal are required. Dispose of the syringe as instructed by your doctor, nurse or pharmacist. 
 
If you use more Accofil than you should 
 
If you use more Accofil than you should, contact your doctor or pharmacist as soon as possible. 
 
If you forget to use Accofil 
 
Do not take a double dose to make up for a forgotten injection. Contact your doctor to discuss when 
you should inject the next dose. 
 



78 
 

If you stop using Accofil 
 
Your doctor will tell you when to stop using Accofil. It is quite normal to have a number of courses of 
treatment with Accofil.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately during treatment: 
 
• if you experience an allergic reaction including weakness, drop in blood pressure, difficulty 
breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face, lips, 
mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea). Hypersensitivity is common 
in patients with cancer; 
• if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of Acute 
Respiratory Distress Syndrome (ARDS). ARDS is uncommon in patients with cancer;  
• if you get left upper belly (abdonimal) pain, pain below the left rib cage or pain at the tip of your 
shoulder since this may relate to a problem with your spleen (enlargement of the spleen 
(splenomegaly) or rupture of the spleen).. if you are being treated for severe chronic neutropenia and 
you have blood in your urine (haematuria). Your doctor may regularly test your urine if you 
experience this side effect or if protein is found in your urine (proteinuria). 
• If you have any of the following or a combination of the following side effects: swelling or 
puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal 
swelling and feeling of fullness, and a general feeling of tiredness. These symptoms generally develop 
in a rapid fashion.  
 
These could be symptoms of an uncommon condition (may affect up to 1 in 100 people) called 
Capillary Leak Syndrome which causes the blood to leak from the small blood vessels into your body 
and needs urgent medical attention.  
 
• If you have a combination of any of the following symptoms: 
  - fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, 
shortness of breath, extreme pain or discomfort and clammy or sweaty skin. 
 
These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a 
severe infection with whole-body inflammatory response which can be life threatening and 
needs urgent medical attention. 
 
if you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients who 
received Accofil. Call your doctor right away if you experience puffiness in your face or ankles, blood 
in your urine or brown-coloured urine or you notice you urinate less than usual 
 
A very frequent side effect of Accofil use is pain in your muscles or bones (musculoskeletal pain), 
which can be helped by taking standard pain relief medicines (analgesics). In patients undergoing a 
stem cell or bone marrow transplant, Graft versus host disease (GvHD) may occur- this is a reaction of 
the donor cells against the patient receiving the transplant; signs and symptoms include rash on the 
palms of your hands and soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your 
eyes, lungs, vagina and joints. Very commonly seen in normal stem cells donors is increase in white 
blood cells (leukocytosis) and decrease of platelets which reduces the ability of blood to clot 
(thrombocytopenia), these will be monitored by your doctor. 
 
 
 



79 
 

Very common side effects (seen in more than 1 in 10 people who take Accofil): 
• 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) 
• decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) 
• low red blood cell count (anaemia) 
• fever (pyrexia) 
• headache 
• diarrhoea 
 
Common side effects (seen in more than 1 in 100 people taking Accofil):  
• inflammation of the lung (bronchitis) 
• upper respiratory tract infection 
•  urinary tract infection 
•  decreased appetite 
•  trouble sleeping (insomnia) 
•  dizziness 
•  decreased feeling of sensitivity, especially in the skin (hypoaesthesia) 
•  tingling or numbness of the hands or feet (paraesthesia) 
•  low blood pressure (hypotension) 
•  high blood pressure (hypertension) 
•  cough 
•  coughing up blood (haemoptysis) 
•  pain in your mouth and throat (oropharyngeal pain) 
•  nose bleeds (epistaxis) 
•  constipation 
•  oral pain 
•  enlargement of the liver (hepatomegaly) 
•  rash 
•  redness of the skin (erythema) 
•  muscle spasm 
•  pain when passing urine (dysuria) 
•  chest pain 
•  pain 
•  generalised weakness (asthenia) 
•  generally feeling unwell (malaise) 
•  swelling in the hands and feet (oedema peripheral) 
•  increase of certain enzymes in the blood 
•  changes in blood chemistry 
•  transfusion reaction 
 
Uncommon side effects (seen in more than 1 in 1000 people taking Accofil):  
•  increase in white blood cells (leukocytosis) 
•  allergic reaction (hypersensitivity) 
•  rejection of transplanted bone marrow (graft versus host disease) 
•  high uric acid levels in the blood, which may cause gout (hyperuricaemia) (Blood uric acid 

increased) 
•  liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) 
•  lungs do not function as they should, causing breathlessness (respiratory failure) 
•  swelling and/or fluid in the lungs (pulmonary oedema) 
•  inflammation of the lungs (interstitial lung disease) 



80 
 

•  abnormal x-rays of the lungs (lung infiltration) 
•  bleeding from the lung (pulmonary haemorrhage) 
•  lack of absorption of oxygen in the lung (hypoxia) 
•  bumpy skin rash (rash macuo-papular) 
•  disease which causes bones to become less dense, making them weaker, more brittle and likely 

to break (osteoporosis) 
•  injection site reaction 
 
Rare side effects (seen in more than 1 in 10,000 people taking Accofil): 
• Inflammation of the aorta (the large blood vessel which transports blood from the 

heart to the body), see section 2. 
•  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 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not 
listed in this leaflet. 
 
Reporting of side effects  
 
If you get any side effects, talk to your doctor. 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 Accofil 
 
Keep out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and on the pre-filled 
syringe after EXP. The expiry date refers to the last day of the month. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze. 
 
The syringe can be removed from the refrigerator and left at room temperature (not above 25°C) for a 
single period, that ends within the labelled expiry date, of up to a maximum of 15 days. At the end of 
this period, the product should not be put back in the refrigerator and should be disposed of. 
 
Keep the pre-filled syringe in the carton in order to protect from light. 
 
Do not use Accofil if you notice it is cloudy, or there is discoloration or there are particles in it. 
 
Do not put the cover back on used needles, as you may accidentally prick yourself. Medicines should 
not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of 
medicines no longer required. These measures will help to protect the environment. 
 
 

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


81 
 

6. Contents of the pack and other information 
 
What Accofil contains  
 
- The active substance is filgrastim. Each pre-filled syringe contains 48 MU (480 micrograms) 
filgrastim in 0.5 ml, corresponding to 0.96 mg/ml.  
- The other ingredients are acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 80 and water 
for injections. 
 
What Accofil looks like and contents of the pack 
 
Accofil is a clear colourless solution for injection or infusion in a pre-filled syringe marked with 1/40 
printed markings from 0.1 mL to 1 mL on the syringe barrel, with an injection needle. Each pre-filled 
syringe contains 0.5 ml of solution. 
 
Accofil is available in packs containing 1, 3, 5, 7 and 10 pre-filled syringes, with or without prefixed 
needle safety guard and alcohol swabs.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
Manufacturer 
Accord Healthcare Limited 
Sage House, 319 Pinner Road 
North Harrow,  
Middlesex, HA1 4HF 
United Kingdom 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland      
 
Accord Healthcare B.V.,  
Winthontlaan 200,  
3526 KV Utrecht,  
The Netherlands                                                                                                                           
 
 For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

AT / BE / BG / CY / CZ / DE / DK /  
EE / EL / FI / HR / HU / IS / LT /  
LV / LX/ MT / NL / NO / PT /  
PL / RO / SE / SI / SK / UK/ ES 
Accord Healthcare S.L.U. 
Tel: +34 93 301 00 64 
 

FR 
Accord Healthcare France SAS  
+33 3 20 40 17 70 
 
 
 

 IT 
Accord Healthcare Limited 
Tel: +39 02 94323700 
 



82 
 

 
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  
 
--------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for medical or healthcare professionals only:  
 
 
Accofil does not contain any preservative. In view of the possible risk of microbial contamination, 
Accofil syringes are for single use only. 
 
Accidental exposure to freezing temperatures for up to 24 hours does not affect the stability of 
Accofil. If exposure has been greater than 24 hours or frozen more than once then Accofil should NOT 
be used.  
 
In order to improve traceability of granulocyte-colony stimulating factors, the product name (Accofil) 
and batch number of the administered product should be clearly recorded in the patient file 
 
Accofil 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, Accofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU 
(2 µg) per ml is not recommended at any time. 
 
The solution should be visually inspected prior to use. Only clear solutions without particles should be 
used.  
 
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per ml, human 
serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final 
injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 µg) should be given with 0.2 
ml of 200 mg/ml (20%) human albumin solution added. 
 
When diluted in 5% glucose, Accofil 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. 
 
Using the pre-filled syringe with a needle safety guard  
 
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not 
affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has 
been given and the plunger cannot be depressed any further. While maintaining pressure on the 
plunger, remove the syringe from the patient. The needle safety guard will cover the needle when 
releasing the plunger.  
 
Using the pre-filled syringe without a needle safety guard 
 



83 
 

Administer the dose as per standard protocol. 
 
Disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
{'Title': '1. what accofil is and what it is used for', 'Section_Content': 'what accofil is accofil contains the active ingredient filgrastim. filgrastim is a protein produced in bacteria called escherichia coli by recombinant dna technology. it belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocyte-colony stimulating factor [g-csf]) produced by your own body. filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to produce more white blood cells that help fight infection. what accofil is used for your doctor has prescribed accofil for you to help your body make more white blood cells. your doctor will tell you why you are being treated with accofil. accofil is useful in several different conditions which are: - chemotherapy - bone marrow transplantation - severe chronic neutropenia (low number of a type of white blood cells) - neutropenia (low number of a type of white blood cells) in patients with hiv infection - peripheral blood stem cell mobilisation (to stimulate stem cells to enter the blood stream to be collected and used in bone marrow transplantation).', 'Entity_Recognition': [{'Text': 'accofil', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the active ingredient filgrastim', 'Type': 'TREATMENT', 'BeginOffset': 33, 'EndOffset': 65}, {'Id': 4, 'BeginOffset': 67, 'EndOffset': 77, 'Score': 0.985405683517456, 'Text': 'filgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a protein', 'Type': 'PROBLEM', 'BeginOffset': 81, 'EndOffset': 90}, {'Text': 'bacteria', 'Type': 'PROBLEM', 'BeginOffset': 103, 'EndOffset': 111}, {'Text': 'escherichia coli', 'Type': 'PROBLEM', 'BeginOffset': 119, 'EndOffset': 135}, {'Text': 'a natural protein', 'Type': 'TEST', 'BeginOffset': 241, 'EndOffset': 258}, {'Text': 'granulocyte', 'Type': 'TEST', 'BeginOffset': 260, 'EndOffset': 271}, {'Id': 5, 'BeginOffset': 334, 'EndOffset': 344, 'Score': 0.5107768177986145, 'Text': 'filgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 0, 'BeginOffset': 360, 'EndOffset': 371, 'Score': 0.7459907531738281, 'Text': 'bone marrow', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'new blood cells', 'Type': 'TREATMENT', 'BeginOffset': 390, 'EndOffset': 405}, {'Text': 'white blood cells', 'Type': 'TEST', 'BeginOffset': 432, 'EndOffset': 449}, {'Id': 7, 'BeginOffset': 466, 'EndOffset': 475, 'Score': 0.8305028080940247, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.78379887342453}]}, {'Id': 6, 'BeginOffset': 529, 'EndOffset': 536, 'Score': 0.4273805618286133, 'Text': 'accofil', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'white blood cells', 'Type': 'TEST', 'BeginOffset': 573, 'EndOffset': 590}, {'Text': 'accofil', 'Type': 'TREATMENT', 'BeginOffset': 649, 'EndOffset': 656}, {'Id': 12, 'BeginOffset': 721, 'EndOffset': 733, 'Score': 0.8367742896080017, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 736, 'EndOffset': 763, 'Score': 0.5119388699531555, 'Text': 'bone marrow transplantation', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': 'severe chronic neutropenia', 'Type': 'PROBLEM', 'BeginOffset': 766, 'EndOffset': 792}, {'Id': 14, 'BeginOffset': 818, 'EndOffset': 835, 'Score': 0.30443134903907776, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 839, 'EndOffset': 850, 'Score': 0.9414324164390564, 'Text': 'neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.907231867313385}]}, {'Id': 15, 'BeginOffset': 876, 'EndOffset': 893, 'Score': 0.5016265511512756, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 912, 'EndOffset': 967, 'Score': 0.41848888993263245, 'Text': 'hiv infection - peripheral blood stem cell mobilisation', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 972, 'EndOffset': 992, 'Score': 0.5800941586494446, 'Text': 'stimulate stem cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'the blood stream', 'Type': 'TEST', 'BeginOffset': 1002, 'EndOffset': 1018}, {'Id': 18, 'BeginOffset': 1047, 'EndOffset': 1074, 'Score': 0.6723216772079468, 'Text': 'bone marrow transplantation', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}]}
{'Title': '2. what you need to know before you use accofil', 'Section_Content': "do not use accofil - if you are allergic (hypersensitive) to filgrastim or any of the other ingredients of this medicine (listed in section 6). warnings and precautions 57 talk to your doctor, pharmacist or nurse before using accofil: please tell your doctor before starting treatment if you have: sickle cell anaemia, accofil may cause sickle cell crisis. osteoporosis (bone disease) please tell your doctor immediately during treatment with accofil, if you: get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder (these may be symptoms of enlarge spleen (splenomegaly) or possibly rupture of spleen). notice unusual bleeding or bruising that may be (these may be symptoms of a decrease in blood platelets (thrombocytopenia), with a reduced ability of your blood to clot. have sudden signs of allergy such as rash, itching or hives of skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing as these could be a signs of severe allergic reaction. experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual (glomerulonephritis). the needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may cause an allergic reaction. inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. the symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. tell your doctor if you experience these symptoms. loss of response to filgrastim if you experience a loss of response or failure to maintain a response with filgrastim treatment, your doctor will investigate the reasons why including whether you have developed antibodies which neutralise filgrastim's activity your doctor may want to monitor you closely, see section 4 of the package leaflet. if you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the blood (leukaemia, myelodysplastic syndrome (mds)) you should talk to your doctor about your risks of developing cancers of the blood and what testing should be done. if you develop or are likely to develop cancers of the blood, you should not use accofil, unless instructed by your doctor. if you are a stem cell donor, you must be aged between16 and 60 years. take special care with other products that stimulate white blood cells accofil 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 accofil you should not receive accofil in the 24 hours before and the 24 hours after receiving chemotherapy. please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. pregnancy and breast-feeding accofil has not been tested in pregnant women. it is important to tell your doctor if you: are pregnant or breast-feeding; 58 think you may be pregnant; or are planning to have a baby. it is unknown whether filgrastim passes over into the breast milk. therefore, your doctor may decide that you should not use this medicine if you are breast-feeding. driving and using machines accofil may have a minor influence on your ability to drive and use machines. this medicine may cause dizziness. it is advisable to wait and see how you feel after taking accofil and before driving or operating machinery. accofil contains sorbitol and sodium this medicine contains sorbitol. if you have been told by your doctor that you have an intolerance to some sugars (fructose), contact your doctor before taking this medicine. this medicine also contains sodium less than 1mmol sodium (0.035 mg) per dose, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately during treatment: if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face, lips, mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea). hypersensitivity is common in patients with cancer; if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of acute respiratory distress syndrome (ards). ards is uncommon in patients with cancer; if you get left upper belly (abdonimal) pain, pain below the left rib cage or pain at the tip of your shoulder since this may relate to a problem with your spleen (enlargement of the spleen (splenomegaly) or rupture of the spleen).. if you are being treated for severe chronic neutropenia and you have blood in your urine (haematuria). your doctor may regularly test your urine if you experience this side effect or if protein is found in your urine (proteinuria). if you have any of the following or a combination of the following side effects: swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. these symptoms generally develop in a rapid fashion. these could be symptoms of an uncommon condition (may affect up to 1 in 100 people) called capillary leak syndrome which causes the blood to leak from the small blood vessels into your body and needs urgent medical attention. if you have a combination of any of the following symptoms: - fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, shortness of breath, extreme pain or discomfort and clammy or sweaty skin. these could be symptoms of a condition called "sepsis" (also called "blood poisoning"), a severe infection with whole-body inflammatory response which can be life threatening and needs urgent medical attention. if you experience kidney injury (glomerulonephritis). kidney injury has been seen in patients who received accofil. call your doctor right away if you experience puffiness in your face or ankles, blood in your urine or brown-coloured urine or you notice you urinate less than usual a very frequent side effect of accofil use is pain in your muscles or bones (musculoskeletal pain), which can be helped by taking standard pain relief medicines (analgesics). in patients undergoing a stem cell or bone marrow transplant, graft versus host disease (gvhd) may occur- this is a reaction of the donor cells against the patient receiving the transplant; signs and symptoms include rash on the palms of your hands and soles of your feet and ulcer and sores in your mouth, gut, liver, skin, or your eyes, lungs, vagina and joints. very commonly seen in normal stem cells donors is increase in white blood cells (leukocytosis) and decrease of platelets which reduces the ability of blood to clot (thrombocytopenia), these will be monitored by your doctor. very common side effects (seen in more than 1 in 10 people who take accofil): 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) decrease of platelets which reduces the ability of blood to clot (thrombocytopenia) low red blood cell count (anaemia) fever (pyrexia) headache diarrhoea common side effects (seen in more than 1 in 100 people taking accofil): inflammation of the lung (bronchitis) upper respiratory tract infection urinary tract infection decreased appetite trouble sleeping (insomnia) dizziness decreased feeling of sensitivity, especially in the skin (hypoaesthesia) tingling or numbness of the hands or feet (paraesthesia) low blood pressure (hypotension) high blood pressure (hypertension) cough coughing up blood (haemoptysis) pain in your mouth and throat (oropharyngeal pain) nose bleeds (epistaxis) constipation oral pain enlargement of the liver (hepatomegaly) rash redness of the skin (erythema) muscle spasm pain when passing urine (dysuria) chest pain pain generalised weakness (asthenia) generally feeling unwell (malaise) swelling in the hands and feet (oedema peripheral) increase of certain enzymes in the blood changes in blood chemistry transfusion reaction uncommon side effects (seen in more than 1 in 1000 people taking accofil): increase in white blood cells (leukocytosis) allergic reaction (hypersensitivity) rejection of transplanted bone marrow (graft versus host disease) high uric acid levels in the blood, which may cause gout (hyperuricaemia) (blood uric acid increased) liver damage caused by blocking of the small veins within the liver (veno-occlusive disease) lungs do not function as they should, causing breathlessness (respiratory failure) swelling and/or fluid in the lungs (pulmonary oedema) 66 inflammation of the lungs (interstitial lung disease) abnormal x-rays of the lungs (lung infiltration) bleeding from the lung (pulmonary haemorrhage) lack of absorption of oxygen in the lung (hypoxia) bumpy skin rash (rash macuo-papular) disease which causes bones to become less dense, making them weaker, more brittle and likely to break (osteoporosis) injection site reaction rare side effects (seen in more than 1 in 10,000 people taking accofil): inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. 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 if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any side effects not listed in this leaflet. reporting of side effects if you get any side effects, talk to your doctor. 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.', 'Entity_Recognition': [{'Text': 'accofil', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 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{'Title': '5. how to store accofil', 'Section_Content': 'keep out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and on the pre-filled syringe after exp. the expiry date refers to the last day of the month. store in a refrigerator (2 - 8). do not freeze. the syringe can be removed from the refrigerator and left at room temperature (not above 25) for a single period, that ends within the labelled expiry date, of up to a maximum of 15 days. at the end of this period, the product should not be put back in the refrigerator and should be disposed of. keep the pre-filled syringe in the carton in order to protect from light. do not use accofil if you notice it is cloudy, or there is discoloration or there are particles in it. do not put the cover back on used needles, as you may accidentally prick yourself. medicines should not be disposed of via wastewater or household waste. ask your pharmacist how to dispose of medicines no longer required. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'accofil', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 56, 'EndOffset': 69}, {'Text': 'the syringe', 'Type': 'TREATMENT', 'BeginOffset': 270, 'EndOffset': 281}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 359, 'EndOffset': 361}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 449, 'EndOffset': 451}, {'Text': 'the pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 572, 'EndOffset': 594}, {'Text': 'the carton', 'Type': 'TREATMENT', 'BeginOffset': 598, 'EndOffset': 608}, {'Text': 'accofil', 'Type': 'TREATMENT', 'BeginOffset': 652, 'EndOffset': 659}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 680, 'EndOffset': 686}, {'Id': 0, 'BeginOffset': 700, 'EndOffset': 713, 'Score': 0.4894590675830841, 'Text': 'discoloration', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'needles', 'Type': 'TREATMENT', 'BeginOffset': 778, 'EndOffset': 785}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 827, 'EndOffset': 836}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 936, 'EndOffset': 945}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 966, 'EndOffset': 980}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what accofil contains - the active substance is filgrastim. each pre-filled syringe contains 30 mu (300 micrograms) filgrastim in 0.5 ml, corresponding to 0.6 mg/ml. - the other ingredients are acetic acid, sodium hydroxide, sorbitol (e420), polysorbate 80 and water for injections. what accofil looks like and contents of the pack accofil is a clear colourless solution for injection or infusion in a pre-filled syringe marked with 1/40 printed markings from 0.1 ml to 1 ml on the syringe barrel, with an injection needle. each pre-filled syringe contains 0.5 ml of solution. accofil is available in packs containing 1, 3, 5, 7 and 10 pre-filled syringes, with or without prefixed needle safety guard and alcohol swabs. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'accofil', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 48, 'EndOffset': 58, 'Score': 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