ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
2.
Each ml of solution for injection or infusion contains 60 million international units [MIU] (600 µg) of
filgrastim.
Each pre-filled syringe contains 30 MIU (300 µg) of filgrastim in 0.5 ml solution for injection or
infusion.
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced in
Escherichia coli
K802 by recombinant DNA technology.
Excipient: Each ml of solution contains 50 mg of sorbitol.
For a full list of excipients, see section 6.1.
3.
Solution for injection or infusion
Clear, colourless solution.
4.
Ratiograstim is indicated for the reduction in the duration of neutropenia and the incidence of febrile
neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the
exception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in the
duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow
transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and
efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Ratiograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).
In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an
absolute neutrophil count (ANC) of ≤ 0.5 x 10
9
/l, and a history of severe or recurrent infections, long
term administration of Ratiograstim is indicated to increase neutrophil counts and to reduce the
incidence and duration of infection-related events.
Ratiograstim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x
10
9
/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when
other options to manage neutropenia are inappropriate.
Special requirements
Filgrastim therapy should only be given in collaboration with an oncology centre which has
experience in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the
necessary diagnostic facilities. The mobilisation and apheresis procedures should be performed in
2
collaboration with an oncology-haematology centre with acceptable experience in this field and where
the monitoring of haematopoietic progenitor cells can be correctly performed.
Established cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not
be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a
daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/ml (5%)
solution for infusion given over 30 minutes (see section 6.6 for instructions on dilution).
The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose
administration that intravenous dosing may shorten the duration of effect. The clinical relevance of
this finding to multiple dose administration is not clear. The choice of route should depend on the
individual clinical circumstance. In randomised clinical trials, a subcutaneous dose of 23 MIU
(230 μg)/m
2
/day (4.0 to 8.4 μg/kg/day) was used.
Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the
neutrophil count has recovered to the normal range. Following established chemotherapy for solid
tumours, lymphomas and lymphoid leukaemias, it is expected that the duration of treatment required
to fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute
myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on
the type, dose and schedule of cytotoxic chemotherapy used.
In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen
1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response,
filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil
count has recovered to the normal range. Premature discontinuation of filgrastim therapy prior to the
time of the expected neutrophil nadir is not recommended.
In patients treated with myeloablative therapy followed by bone marrow transplantation
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or
24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous
infusion. Filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion (see
section 6.6 for instructions on dilution).
The first dose of filgrastim should not be administered less than 24 hours following cytotoxic
chemotherapy and within 24 hours of bone marrow infusion.
Once the neutrophil nadir has been passed the daily dose of filgrastim should be titrated against the
neutrophil response as follows:
Neutrophil count
Filgrastim dose adjustment
> 1.0 x 10
9
/l for 3 consecutive days
Reduce to 0.5 MIU (5 µg)/kg/day
Then, if ANC remains > 1.0 x 10
9
/l for 3 more
consecutive days
Discontinue filgrastim
If the ANC decreases to < 1.0 x 10
9
/l during the treatment period the dose of filgrastim should be re-
escalated according to the above steps
For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy
followed by autologous peripheral blood progenitor cell transplantation
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU
(10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection
for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 ml of glucose 50 mg/ml
(5%) solution for infusion (see section 6.6 for instructions on dilution). Timing of leukapheresis: 1 or
3
2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses
may be necessary. Filgrastim dosing should be maintained until the last leukapheresis.
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is
0.5 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of
chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to
the normal range. Leukapheresis should be performed during the period when the ANC rises from <
0.5 x 10
9
/l to > 5.0 x 10
9
/l. For patients who have not had extensive chemotherapy, one leukapheresis
is often sufficient. In other circumstances, additional leukaphereses are recommended.
For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell
transplantation
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/day
subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued
until day 6 if needed in order to collect 4 x 10
6
CD34
+
cells/kg recipient bodyweight.
In patients with severe chronic neutropenia (SCN)
Congenital neutropenia
The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in
divided doses.
Idiopathic or cyclic neutropenia
The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously as a single dose or in
divided doses.
Dose adjustment
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has
reached and can be maintained at more than 1.5 x 10
9
/l. When the response has been obtained, the
minimal effective dose to maintain this level should be established. Long-term daily administration is
required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose
may be doubled or halved depending upon the patient's response. Subsequently the dose may be
individually adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 10
9
/l
and 10 x 10
9
/l. A faster schedule of dose escalation may be considered in patients presenting with
severe infections. In clinical trials, 97% of patients who responded had a complete response at doses of
2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU
(24 μg)/kg/day in patients with SCN has not been established.
In patients with HIV infection
For reversal of neutropenia
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous
injection with titration up to a maximum of 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is
reached and can be maintained (ANC > 2.0 x10
9
/l). In clinical studies, > 90% of patients responded at
these doses, achieving reversal of neutropenia in a median of 2 days.
In a small number of patients (< 10%), doses up to 1.0 MIU (10 μg)/kg/day were required to achieve
reversal of neutropenia.
For maintaining normal neutrophil counts
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU
(300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary,
as determined by the patient's ANC, to maintain the neutrophil count at > 2.0 x 10
9
/l. In clinical
studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC
4
> 2.0 x 10
9
/l, with the median dose frequency being 3 days per week. Long-term administration may
be required to maintain the ANC > 2.0 x 10
9
/l.
Special populations
Elderly patients
Clinical trials with filgrastim have included a small number of elderly patients but special studies have
not been performed in this group and therefore specific dosage recommendations cannot be made.
Patients with renal or hepatic impairment
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it
exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals.
Dose adjustment is not required in these circumstances.
Paediatric use in the SCN and cancer settings
Sixty-five percent of the patients studied in the SCN trial programme were under 18 years of age. The
efficacy of treatment was clear for this age group, which included most patients with congenital
neutropenia. There were no differences in the safety profiles for paediatric patients treated for severe
chronic neutropenia.
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are
similar in both adults and children receiving cytotoxic chemotherapy.
The dosage recommendations in paediatric patients are the same as those in adults receiving
myelosuppressive cytotoxic chemotherapy.
Hypersensitivity to the active substance or to any of the excipients.
Special warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established
dosage regimens (see below).
Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman's
syndrome) with abnormal cytogenetics (see below).
Special precautions in patients with acute myeloid leukaemia
Malignant cell growth
Granulocyte-colony stimulating factor can promote growth of myeloid cells
in vitro
and similar effects
may also be seen on some non-myeloid cells
in vitro
.
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or
chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for
use in these conditions. Particular care should be taken to distinguish the diagnosis of blast
transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be
administered with caution.
The safety and efficacy of filgrastim administration in
de novo
AML patients aged < 55 years with
good cytogenetics [t(8;21), t(15;17), and inv(16)] have not been established.
5
Other special precautions
Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases
who undergo continuous therapy with filgrastim for more than 6 months.
Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after G-
CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at
higher risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with
radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary
signs of Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and
appropriate treatment given in these cases.
Special precautions in cancer patients
Leukocytosis
White blood cell counts of 100 x 10
9
/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 10
9
/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 10
9
/l.
Risks associated with increased doses of chemotherapy
Special caution should be used when treating patients with high dose chemotherapy because improved
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead
to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please refer
to the Summary of Product Characteristics of the specific chemotherapy agents used).
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to
myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy
(e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and
anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should
be taken when administering single or combination chemotherapeutic agents which are known to
cause severe thrombocytopenia.
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of
thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been
studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil
counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration
by tumour).
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF
after allogeneic bone marrow transplantation (see section 5.1).
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been
associated with transient positive bone-imaging findings. This should be considered when interpreting
bone-imaging results.
6
Special precautions in patients undergoing peripheral blood progenitor cell mobilisation
Mobilisation
There are no prospectively randomised comparisons of the two recommended mobilisation methods
(filgrastim alone or in combination with myelosuppressive chemotherapy) within the same patient
population. The degree of variation between individual patients and between laboratory assays of
CD34
+
cells mean that direct comparison between different studies is difficult. It is therefore difficult
to recommend an optimum method. The choice of mobilisation method should be considered in
relation to the overall objectives of treatment for an individual patient.
Prior exposure to cytotoxic agents
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient
mobilisation of PBPC to achieve the recommended minimum yield (2.0 x 10
6
CD34
+
cells/kg) or
acceleration of platelet recovery to the same degree.
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may
adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and
carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation,
may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU
together with filgrastim has been shown to be effective for progenitor mobilisation. When a peripheral
blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell mobilisation
procedure early in the treatment course of the patient. Particular attention should be paid to the number
of progenitors mobilised in such patients before the administration of high-dose chemotherapy. If
yields are inadequate, as measured by the criteria above, alternative forms of treatment not requiring
progenitor support should be considered.
Assessment of progenitor cell yields
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular
attention should be paid to the method of quantitation. The results of flow cytometric analysis of
CD34
+
cell numbers vary depending on the precise methodology used and therefore, recommendations
of numbers based on studies in other laboratories need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34
+
cells re-infused and the rate of
platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.
The recommendation of a minimum yield of 2.0 x 10
6
CD34
+
cells/kg is based on published
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield
appear to correlate with more rapid recovery, those below with slower recovery.
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilisation
Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be
considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory
eligibility criteria for stem cell donation. Particular attention should be paid to haematological values
and infectious diseases.
The safety and efficacy of filgrastim
have not been assessed in normal donors < 16 years or > 60
years.
Transient thrombocytopenia (platelets < 100 x 10
9
/l) following filgrastim administration and
leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets < 50 x
10
9
/l were reported and attributed to the leukapheresis procedure.
7
If more than one leukapheresis is required, particular attention should be paid to donors with platelets
< 100 x 10
9
/l prior to leukapheresis; in general apheresis should not be performed if platelets < 75 x
10
9
/l.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects
in haemostasis.
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte
counts rise to > 70 x10
9
/l.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices
return to normal.
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The
significance of these changes in terms of the development of haematological malignancy is unknown.
Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant myeloid clone
can not be excluded. It is recommended that the apheresis centre perform a systematic record and
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or
patients reporting left upper abdominal pain or shoulder tip pain.
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates,
dyspnoea and hypoxia) have been reported very rarely in postmarketing experience. In case of
suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should
be considered and appropriate medical care given.
Special precautions in recipients of allogeneic PBPC mobilised with filgrastim
Current data indicate that immunological interactions between the allogeneic PBPC graft and the
recipient may be associated with an increased risk of acute and chronic GvHD when compared with
bone marrow transplantation.
Special precautions in SCN patients
Blood cell counts
Platelet counts should be monitored closely, especially during the first few weeks of filgrastim
therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in
patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm
3
.
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 severe chronic neutropenias to distinguish them from
other haematopoietic disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia.
Complete blood cell counts with differential and platelet counts and an evaluation of bone marrow
morphology and karyotype should be performed prior to treatment.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in
clinical trial patients with SCN treated with filgrastim. This observation has only been made in
patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease
and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had
normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including
8
monosomy 7, on routine repeat evaluation. If patients with SCN develop abnormal cytogenetics, the
risks and benefits of continuing filgrastim should be carefully weighed; filgrastim should be
discontinued if MDS or leukaemia occur. It is currently unclear whether long-term treatment of
patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic
transformation. It is recommended to perform morphologic and cytogenetic bone marrow
examinations in patients at regular intervals (approximately every 12 months).
Other special precautions
Causes of transient neutropenia such as viral infections should be excluded.
Splenic enlargement is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of
patients in studies were documented as having palpable splenomegaly. Increases in volume, measured
radiographically, occurred early during filgrastim therapy and tended to plateau. Dose reductions were
noted to slow or stop the progression of splenic enlargement and in 3% of patients a splenectomy was
required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to detect
abnormal increases in splenic volume.
Haematuria/proteinuria occurred in a small number of patients. Regular urinanalysis should be
performed to monitor this event.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been
established.
Special precautions in patients with HIV infection
Blood cell counts
ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Some
patients may respond very rapidly and with a considerable increase in neutrophil count to the initial
dose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of
filgrastim
administration. Thereafter, it is recommended that the ANC is measured at least twice
weekly for the first two weeks and subsequently once per week or once every other week during
maintenance therapy. During intermittent dosing with 30 MIU (300 μg)/day of filgrastim, there can be
wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or nadir
ANC, it is recommended that blood samples are taken for ANC measurement immediately prior to any
scheduled dosing with filgrastim.
Risk associated with increased doses of myelosuppressive medicinal products
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to
myelosuppressive medicinal products. As a result of the potential to receive higher doses or a greater
number of these medicinal products with filgrastim therapy, the patient may be at higher risk of
developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see
above).
Infections and malignancies causing myelosuppression
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as
Mycobacterium
avium
complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating
infections or malignancy, consider appropriate therapy for treatment of the underlying condition in
addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on
neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established.
Special precautions in sickle cell disease
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with
sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in
patients with sickle cell disease and only after careful evaluation of the potential risks and benefits.
Excipients
9
Ratiograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should
not use this medicinal product.
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.
There are no adequate data from the use of filgrastim in pregnant women. There are reports in the
literature where the transplacental passage of filgrastim in pregnant women has been demonstrated.
Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown. Filgrastim should not be used during pregnancy unless clearly necessary.
It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk
has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to
continue/discontinue therapy with filgrastim should be made taking into account the benefit of breast-
feeding to the child and the benefit of filgrastim therapy to the woman.
Filgrastim has minor or moderate influence on the ability to drive and use machines. If the patient is
experiencing fatigue, caution is advised when driving a car or operating machinery.
During clinical studies 541 cancer patients and 188 healthy volunteers were exposed to Ratiograstim.
The safety profile of Ratiograstim observed in these clinical studies was consistent with that reported
with the reference product used in these studies.
The following undesirable effects and their frequencies have been observed under treatment with
filgrastim based on published information.
The assessment of undesirable effects is based on the following frequency data:
Very common: ≥1/10
Common: ≥1/100, <1/10
Uncommon: ≥1/1,000, <1/100
Rare: ≥1/10,000, <1/1,000
Very rare:
<1/10,000
Not known:
cannot be estimated from the available data
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
10
In cancer patients
In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended
dose were mild or moderate musculoskeletal pain, occurring in 10%, and severe musculoskeletal pain
in 3% of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent
undesirable effects include urinary abnormalities predominantly mild or moderate dysuria.
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of
frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included nausea
and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, headache, cough, skin rash, chest pain,
generalised weakness, sore throat, constipation and unspecified pain.
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase (LDH),
alkaline phosphatase, serum uric acid and gamma-glutamyltransferase (GGT) occurred with filgrastim
in approximately 50%, 35%, 25%, and 10% of patients respectively, at recommended doses.
Transient decreases in blood pressure, not requiring clinical treatment, have been reported
occasionally.
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone
marrow transplantation (see section 5.1).
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been
reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone
marrow transplantation. The causal association with filgrastim has not been established.
Very rare events of cutaneous vasculitis have been reported in patients treated with filgrastim. The
mechanism of vasculitis in patients receiving filgrastim is unknown.
The occurrence of Sweet's syndrome (acute febrile dermatosis) has been reported occasionally.
However, since a significant percentage of these patients were suffering from leukaemia, a condition
known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been
established.
Exacerbation of rheumatoid arthritis has been observed in individual cases.
Pseudogout has been reported in patients with cancer treated with filgrastim.
Rare pulmonary undesirable effects including interstitial pneumonia, pulmonary oedema and
pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or adult
respiratory distress syndrome (ARDS) which may be fatal (see section 4.4).
Allergic Reactions: Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema,
dyspnoea and hypotension, occurring on initial or subsequent treatment, have been reported in patients
receiving filgrastim. Overall, reports were more common after IV administration. In some cases,
symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be
permanently discontinued in patients who experience a serious allergic reaction.
Isolated cases of sickle cells crises have been reported in patients with sickle cell disease (see section
4.4).
11
System organ class
Frequency
Undesirable effect
Metabolism and nutrition
disorders
Very common
Elevated alkaline phosphatase,
elevated LDH, elevated uric acid
Nervous system disorders
Common
Headache
Vascular disorders
Rare
Vascular disorder
Respiratory, thoracic and
mediastinal disorders
Common
Cough, sore throat
Very rare
Pulmonary infiltrates
Gastrointestinal disorders
Very common
Nausea/Vomiting
Common
Constipation, anorexia,
diarrhoea, mucositis
Hepatobiliary disorders
Very common
Elevated GGT
Skin and subcutaneous tissue
disorders
Common
Alopecia, skin rash
Very rare
Sweet's syndrome, cutaneous
vasculitis
Musculoskeletal and connective
tissue disorders
Very common
Chest pain, musculoskeletal pain
Very rare
Rheumatoid arthritis
exacerbation
Renal and urinary disorders
Very rare
Urinary abnormalities
General disorders and
administration site conditions
Common
Fatigue, generalised weakness
Uncommon
Unspecified pain
Very rare
Allergic reaction
In peripheral blood progenitor cell mobilisation in normal donors
The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal pain.
Leukocytosis (WBC > 50 x 10
9
/l) was observed in 41% of donors and transient thrombocytopenia
(platelets < 100 x 10
9
/l) following filgrastim and leukapheresis was observed in 35% of donors.
Transient, minor increases in alkaline phosphatase, LDH, SGOT (serum glutamic oxaloacetic
transaminase) and uric acid have been reported in normal donors receiving filgrastim; these were
without clinical sequelae.
Exacerbation of arthritic symptoms has been observed very rarely.
Symptoms suggestive of severe allergic reactions have been reported very rarely.
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture
have been reported in healthy donors and patients following administration of G-CSFs (see section
4.4).
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration,
dyspnoea and hypoxia) have been reported in postmarketing experience (see section 4.4).
12
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Very common
Leukocytosis, thrombocytopenia
Uncommon
Spleen disorder
Metabolism and nutrition
disorders
Common
Elevated alkaline phosphatase,
elevated LDH
Uncommon
SGOT increased,
hyperuricaemia
Nervous system disorders
Very common
Headache
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
Uncommon
Rheumatoid arthritis
exacerbation
General disorders and
administration site conditions
Uncommon
Severe allergic reaction
In SCN patients
Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some their
frequencies tend to decrease with time.
The most frequent undesirable effects attributable to filgrastim were bone pain, and general
musculoskeletal pain.
Other undesirable effects seen include splenic enlargement, which may be progressive in a minority of
cases and thrombocytopenia. Headache and diarrhoea have been reported shortly after starting
filgrastim therapy, typically in less than 10% of patients. Anaemia and epistaxis have also been
reported.
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase
and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been
seen.
patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and
rash.
During long term use, cutaneous vasculitis has been reported in 2% of SCN patients. There have been
very few instances of proteinuria/haematuria.
13
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Very common
Anaemia, splenomegaly
Common
Thrombocytopenia
Uncommon
Spleen disorder
Metabolism and nutrition
disorders
Very common
Decreased glucose, elevated
alkaline phosphatase, elevated
LDH, hyperuricaemia
Nervous system disorders
Common
Headache
Respiratory, thoracic and
mediastinal disorders
Very common
Epistaxis
Gastrointestinal disorders
Common
Diarrhoea
Hepatobiliary disorders
Common
Hepatomegaly
Skin and subcutaneous tissue
disorders
Common
Alopecia, cutaneous vasculitis,
injection site pain, rash
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
Common
Osteoporosis
Renal and urinary disorders
Uncommon
Haematuria, proteinuria
In patients with HIV
In clinical studies, the only undesirable effects that were consistently considered to be related to
filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and
myalgia. The incidence of these events was similar to that reported in cancer patients.
Splenic enlargement was reported to be related to filgrastim therapy in < 3% of patients. In all cases
this was mild or moderate on physical examination and the clinical course was benign; no patients had
a diagnosis of hypersplenism and no patients underwent splenectomy. As splenic enlargement is a
common finding in patients with HIV infection and is present to varying degrees in most patients with
AIDS, the relationship to filgrastim treatment is unclear.
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Common
Spleen disorder
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
No case of overdose has been reported.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Colony stimulating factors, ATC code: L03AA02
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils
from the bone marrow. Ratiograstim containing r-metHuG-CSF (filgrastim) causes marked increases
in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some
SCN patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and
basophils relative to baseline; some of these patients may present with eosinophilia or basophilia prior
14
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.
Relative risk (95% CI) of GvHD and TRM following treatment with G-CSF after bone marrow
transplantation
Publication
Period of
study
N
Acute grade
II-IV GvHD
Chronic
GvHD
TRM
Meta-analysis
(2003)
1986-2001
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 bone marrow transplant during this period; some studies used
GM-CSF (granulocyte-macrophage–colony stimulating factor)
b
Analysis includes patients receiving bone marrow transplant during this period
Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normal
donors allows a collection of 4 x 10
6
CD34
+
cells/kg recipient body weight in the majority of the
donors after two leukaphereses. Normal donors are given a dose of a 10 μg/kg/day, administered
subcutaneously for 4 to 5 consecutive days.
Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic
neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a
reduction of infection and related events.
15
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled
dosing of antiviral and/or other myelosuppressive medicinal product. There is no evidence that
patients with HIV infection treated with filgrastim show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown
in vitro
stimulating properties on
human endothelial cells.
The efficacy and safety of Ratiograstim has been assessed in randomised, controlled phase III studies
in breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences
between Ratiograstim and the reference product with regard to duration of severe neutropenia and
incidence of febrile neutropenia.
5.2 Pharmacokinetic properties
Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the
pharmacokinetic profile of Ratiograstim was comparable to that of the reference product after
subcutaneous and intravenous administration.
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous
and intravenous administration. The serum elimination half-life of filgrastim is approximately
3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with filgrastim
over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation,
resulted in no evidence of drug accumulation and comparable elimination half-lives. There is a
positive linear correlation between the dose and the serum concentration of filgrastim, whether
administered intravenously or subcutaneously. Following subcutaneous administration of
recommended doses, serum concentrations were maintained above 10 ng/ml for 8 to 16 hours. The
volume of distribution in blood is approximately 150 ml/kg.
In cancer patients, the pharmacokinetic profile of Ratiograstim and the reference product was
comparable after single and repeated subcutaneous administration.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, genotoxicity and local tolerance.
Preclinical data from conventional studies of repeated dose toxicity revealed the expected
pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow,
extramedullary haematopoiesis and splenic enlargement.
No effect was observed on the fertility of male and female rats or gestation in rats. There is no
evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of
embryo-loss has been observed in rabbits, but no malformation has been seen.
6.
6.1 List of excipients
Acetic acid, glacial
Sodium hydroxide
Sorbitol (E420)
Polysorbate 80
Water for injections
6.2 Incompatibilities
16
Ratiograstim should not be diluted with sodium chloride solution.
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
Diluted filgrastim may be adsorbed to glass and plastic materials except diluted, as mentioned in
section 6.6.
6.3 Shelf life
30 months.
After dilution: Chemical and physical in-use stability of the diluted solution for infusion has been
demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should
be used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
For storage conditions 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 with or without
safety device to prevent needle stick injury and re-use.
Packs containing 1, 5 or 10 pre-filled syringes with 0.5 ml solution for injection or infusion or
multipacks containing 10 (2 packs of 5) pre-filled syringes with 0.5 ml solution for injection or
infusion.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
If required, Ratiograstim may be diluted in glucose 50 mg/ml (5%) solution for infusion.
Dilution to a final concentration less than 0.2 MIU (2 μg) per ml is not recommended at any time.
The solution should be visually inspected prior to use. Only clear solutions without particles should be
used.
For patients treated with filgrastim diluted to concentrations below 1.5 MIU (15 μg) per ml, human
serum albumin (HSA) should be added to a final concentration of 2 mg/ml.
Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MIU (300 μg)
should be given with 0.2 ml of 200 mg/ml (20%) human albumin solution added.
When diluted in glucose 50 mg/ml (5%) solution for infusion, Ratiograstim is compatible with glass
and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene)
and polypropylene.
Ratiograstim does not contain any preservative. In view of the possible risk of microbial
contamination, Ratiograstim syringes are for single use only.
17
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
8.
EU/1/08/444/001
EU/1/08/444/002
EU/1/08/444/003
EU/1/08/444/004
EU/1/08/444/009
EU/1/08/444/010
9.
Date of first authorisation: 15 September 2008.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
18
1.
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
2.
Each ml of solution for injection or infusion contains 60 million international units [MIU] (600 µg) of
filgrastim.
Each pre-filled syringe contains 48 MIU (480 µg) of filgrastim in 0.8 ml solution for injection or
infusion.
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced in
Escherichia coli
K802 by recombinant DNA technology.
Excipient: Each ml of solution contains 50 mg of sorbitol.
For a full list of excipients, see section 6.1.
3.
Solution for injection or infusion
Clear, colourless solution.
4.
Ratiograstim is indicated for the reduction in the duration of neutropenia and the incidence of febrile
neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the
exception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in the
duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow
transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and
efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Ratiograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).
In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an
absolute neutrophil count (ANC) of ≤ 0.5 x 10
9
/l, and a history of severe or recurrent infections, long
term administration of Ratiograstim is indicated to increase neutrophil counts and to reduce the
incidence and duration of infection-related events.
Ratiograstim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x
10
9
/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when
other options to manage neutropenia are inappropriate.
Special requirements
Filgrastim therapy should only be given in collaboration with an oncology centre which has
experience in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the
necessary diagnostic facilities. The mobilisation and apheresis procedures should be performed in
19
collaboration with an oncology-haematology centre with acceptable experience in this field and where
the monitoring of haematopoietic progenitor cells can be correctly performed.
Established cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not
be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a
daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/ml (5%)
solution for infusion given over 30 minutes (see section 6.6 for instructions on dilution).
The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose
administration that intravenous dosing may shorten the duration of effect. The clinical relevance of
this finding to multiple dose administration is not clear. The choice of route should depend on the
individual clinical circumstance. In randomised clinical trials, a subcutaneous dose of 23 MIU
(230 μg)/m
2
/day (4.0 to 8.4 μg/kg/day) was used.
Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the
neutrophil count has recovered to the normal range. Following established chemotherapy for solid
tumours, lymphomas and lymphoid leukaemias, it is expected that the duration of treatment required
to fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute
myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on
the type, dose and schedule of cytotoxic chemotherapy used.
In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen
1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response,
filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil
count has recovered to the normal range. Premature discontinuation of filgrastim therapy prior to the
time of the expected neutrophil nadir is not recommended.
In patients treated with myeloablative therapy followed by bone marrow transplantation
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or
24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous
infusion. Filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion (see
section 6.6 for instructions on dilution).
The first dose of filgrastim should not be administered less than 24 hours following cytotoxic
chemotherapy and within 24 hours of bone marrow infusion.
Once the neutrophil nadir has been passed the daily dose of filgrastim should be titrated against the
neutrophil response as follows:
Neutrophil count
Filgrastim dose adjustment
> 1.0 x 10
9
/l for 3 consecutive days
Reduce to 0.5 MIU (5 µg)/kg/day
Then, if ANC remains > 1.0 x 10
9
/l for 3 more
consecutive days
Discontinue filgrastim
If the ANC decreases to < 1.0 x 10
9
/l during the treatment period the dose of filgrastim should be re-
escalated according to the above steps
For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy
followed by autologous peripheral blood progenitor cell transplantation
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU
(10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection
for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 ml of glucose 50 mg/ml
(5%) solution for infusion (see section 6.6 for instructions on dilution). Timing of leukapheresis: 1 or
20
2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses
may be necessary. Filgrastim dosing should be maintained until the last leukapheresis.
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is
0.5 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of
chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to
the normal range. Leukapheresis should be performed during the period when the ANC rises from <
0.5 x 10
9
/l to > 5.0 x 10
9
/l. For patients who have not had extensive chemotherapy, one leukapheresis
is often sufficient. In other circumstances, additional leukaphereses are recommended.
For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell
transplantation
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/day
subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued
until day 6 if needed in order to collect 4 x 10
6
CD34
+
cells/kg recipient bodyweight.
In patients with severe chronic neutropenia (SCN)
Congenital neutropenia
The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in
divided doses.
Idiopathic or cyclic neutropenia
The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously as a single dose or in
divided doses.
Dose adjustment
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has
reached and can be maintained at more than 1.5 x 10
9
/l. When the response has been obtained, the
minimal effective dose to maintain this level should be established. Long-term daily administration is
required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose
may be doubled or halved depending upon the patient's response. Subsequently the dose may be
individually adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 10
9
/l
and 10 x 10
9
/l. A faster schedule of dose escalation may be considered in patients presenting with
severe infections. In clinical trials, 97% of patients who responded had a complete response at doses of
2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU
(24 μg)/kg/day in patients with SCN has not been established.
In patients with HIV infection
For reversal of neutropenia
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous
injection with titration up to a maximum of 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is
reached and can be maintained (ANC > 2.0 x10
9
/l). In clinical studies, > 90% of patients responded at
these doses, achieving reversal of neutropenia in a median of 2 days.
In a small number of patients (< 10%), doses up to 1.0 MIU (10 μg)/kg/day were required to achieve
reversal of neutropenia.
For maintaining normal neutrophil counts
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal
neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU
(300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary,
as determined by the patient's ANC, to maintain the neutrophil count at > 2.0 x 10
9
/l. In clinical
studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC
21
> 2.0 x 10
9
/l, with the median dose frequency being 3 days per week. Long-term administration may
be required to maintain the ANC > 2.0 x 10
9
/l.
Special populations
Elderly patients
Clinical trials with filgrastim have included a small number of elderly patients but special studies have
not been performed in this group and therefore specific dosage recommendations cannot be made.
Patients with renal or hepatic impairment
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it
exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals.
Dose adjustment is not required in these circumstances.
Paediatric use in the SCN and cancer settings
Sixty-five percent of the patients studied in the SCN trial programme were under 18 years of age. The
efficacy of treatment was clear for this age group, which included most patients with congenital
neutropenia. There were no differences in the safety profiles for paediatric patients treated for severe
chronic neutropenia.
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are
similar in both adults and children receiving cytotoxic chemotherapy.
The dosage recommendations in paediatric patients are the same as those in adults receiving
myelosuppressive cytotoxic chemotherapy.
Hypersensitivity to the active substance or to any of the excipients.
Special warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established
dosage regimens (see below).
Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman's
syndrome) with abnormal cytogenetics (see below).
Special precautions in patients with acute myeloid leukaemia
Malignant cell growth
Granulocyte-colony stimulating factor can promote growth of myeloid cells
in vitro
and similar effects
may also be seen on some non-myeloid cells
in vitro
.
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or
chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for
use in these conditions. Particular care should be taken to distinguish the diagnosis of blast
transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be
administered with caution.
The safety and efficacy of filgrastim administration in
de novo
AML patients aged < 55 years with
good cytogenetics [t(8;21), t(15;17), and inv(16)] have not been established.
22
Other special precautions
Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases
who undergo continuous therapy with filgrastim for more than 6 months.
Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after G-
CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at
higher risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with
radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary
signs of Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and
appropriate treatment given in these cases.
Special precautions in cancer patients
Leukocytosis
White blood cell counts of 100 x 10
9
/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 10
9
/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 10
9
/l.
Risks associated with increased doses of chemotherapy
Special caution should be used when treating patients with high dose chemotherapy because improved
tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead
to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please refer
to the Summary of Product Characteristics of the specific chemotherapy agents used).
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to
myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy
(e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and
anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should
be taken when administering single or combination chemotherapeutic agents which are known to
cause severe thrombocytopenia.
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of
thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been
studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil
counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such
as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration
by tumour).
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF
after allogeneic bone marrow transplantation (see section 5.1).
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been
associated with transient positive bone-imaging findings. This should be considered when interpreting
bone-imaging results.
23
Special precautions in patients undergoing peripheral blood progenitor cell mobilisation
Mobilisation
There are no prospectively randomised comparisons of the two recommended mobilisation methods
(filgrastim alone or in combination with myelosuppressive chemotherapy) within the same patient
population. The degree of variation between individual patients and between laboratory assays of
CD34
+
cells mean that direct comparison between different studies is difficult. It is therefore difficult
to recommend an optimum method. The choice of mobilisation method should be considered in
relation to the overall objectives of treatment for an individual patient.
Prior exposure to cytotoxic agents
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient
mobilisation of PBPC to achieve the recommended minimum yield (2.0 x 10
6
CD34
+
cells/kg) or
acceleration of platelet recovery to the same degree.
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may
adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and
carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation,
may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU
together with filgrastim has been shown to be effective for progenitor mobilisation. When a peripheral
blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell mobilisation
procedure early in the treatment course of the patient. Particular attention should be paid to the number
of progenitors mobilised in such patients before the administration of high-dose chemotherapy. If
yields are inadequate, as measured by the criteria above, alternative forms of treatment not requiring
progenitor support should be considered.
Assessment of progenitor cell yields
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular
attention should be paid to the method of quantitation. The results of flow cytometric analysis of
CD34
+
cell numbers vary depending on the precise methodology used and therefore, recommendations
of numbers based on studies in other laboratories need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34
+
cells re-infused and the rate of
platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.
The recommendation of a minimum yield of 2.0 x 10
6
CD34
+
cells/kg is based on published
experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield
appear to correlate with more rapid recovery, those below with slower recovery.
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilisation
Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be
considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory
eligibility criteria for stem cell donation. Particular attention should be paid to haematological values
and infectious diseases.
The safety and efficacy of filgrastim
have not been assessed in normal donors < 16 years or > 60
years.
Transient thrombocytopenia (platelets < 100 x 10
9
/l) following filgrastim administration and
leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets < 50 x
10
9
/l were reported and attributed to the leukapheresis procedure.
24
If more than one leukapheresis is required, particular attention should be paid to donors with platelets
< 100 x 10
9
/l prior to leukapheresis; in general apheresis should not be performed if platelets < 75 x
10
9
/l.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects
in haemostasis.
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte
counts rise to > 70 x10
9
/l.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices
return to normal.
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The
significance of these changes in terms of the development of haematological malignancy is unknown.
Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant myeloid clone
can not be excluded. It is recommended that the apheresis centre perform a systematic record and
tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture
have been reported in healthy donors and patients following administration of G-CSFs. Some cases of
splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical
examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or
patients reporting left upper abdominal pain or shoulder tip pain.
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates,
dyspnoea and hypoxia) have been reported very rarely in postmarketing experience. In case of
suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should
be considered and appropriate medical care given.
Special precautions in recipients of allogeneic PBPC mobilised with filgrastim
Current data indicate that immunological interactions between the allogeneic PBPC graft and the
recipient may be associated with an increased risk of acute and chronic GvHD when compared with
bone marrow transplantation.
Special precautions in SCN patients
Blood cell counts
Platelet counts should be monitored closely, especially during the first few weeks of filgrastim
therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in
patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm
3
.
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 severe chronic neutropenias to distinguish them from
other haematopoietic disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia.
Complete blood cell counts with differential and platelet counts and an evaluation of bone marrow
morphology and karyotype should be performed prior to treatment.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in
clinical trial patients with SCN treated with filgrastim. This observation has only been made in
patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease
and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had
normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including
25
monosomy 7, on routine repeat evaluation. If patients with SCN develop abnormal cytogenetics, the
risks and benefits of continuing filgrastim should be carefully weighed; filgrastim should be
discontinued if MDS or leukaemia occur. It is currently unclear whether long-term treatment of
patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic
transformation. It is recommended to perform morphologic and cytogenetic bone marrow
examinations in patients at regular intervals (approximately every 12 months).
Other special precautions
Causes of transient neutropenia such as viral infections should be excluded.
Splenic enlargement is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of
patients in studies were documented as having palpable splenomegaly. Increases in volume, measured
radiographically, occurred early during filgrastim therapy and tended to plateau. Dose reductions were
noted to slow or stop the progression of splenic enlargement and in 3% of patients a splenectomy was
required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to detect
abnormal increases in splenic volume.
Haematuria/proteinuria occurred in a small number of patients. Regular urinanalysis should be
performed to monitor this event.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been
established.
Special precautions in patients with HIV infection
Blood cell counts
ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Some
patients may respond very rapidly and with a considerable increase in neutrophil count to the initial
dose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of
filgrastim
administration. Thereafter, it is recommended that the ANC is measured at least twice
weekly for the first two weeks and subsequently once per week or once every other week during
maintenance therapy. During intermittent dosing with 30 MIU (300 μg)/day of filgrastim, there can be
wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or nadir
ANC, it is recommended that blood samples are taken for ANC measurement immediately prior to any
scheduled dosing with filgrastim.
Risk associated with increased doses of myelosuppressive medicinal products
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to
myelosuppressive medicinal products. As a result of the potential to receive higher doses or a greater
number of these medicinal products with filgrastim therapy, the patient may be at higher risk of
developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see
above).
Infections and malignancies causing myelosuppression
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as
Mycobacterium
avium
complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating
infections or malignancy, consider appropriate therapy for treatment of the underlying condition in
addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on
neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established.
Special precautions in sickle cell disease
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with
sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in
patients with sickle cell disease and only after careful evaluation of the potential risks and benefits.
Excipients
26
Ratiograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should
not use this medicinal product.
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.
There are no adequate data from the use of filgrastim in pregnant women. There are reports in the
literature where the transplacental passage of filgrastim in pregnant women has been demonstrated.
Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown. Filgrastim should not be used during pregnancy unless clearly necessary.
It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk
has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to
continue/discontinue therapy with filgrastim should be made taking into account the benefit of breast-
feeding to the child and the benefit of filgrastim therapy to the woman.
Filgrastim has minor or moderate influence on the ability to drive and use machines. If the patient is
experiencing fatigue, caution is advised when driving a car or operating machinery.
During clinical studies 541 cancer patients and 188 healthy volunteers were exposed to Ratiograstim.
The safety profile of Ratiograstim observed in these clinical studies was consistent with that reported
with the reference product used in these studies.
The following undesirable effects and their frequencies have been observed under treatment with
filgrastim based on published information.
The assessment of undesirable effects is based on the following frequency data:
Very common: ≥1/10
Common: ≥1/100, <1/10
Uncommon: ≥1/1,000, <1/100
Rare: ≥1/10,000, <1/1,000
Very rare:
<1/10,000
Not known:
cannot be estimated from the available data
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
27
In cancer patients
In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended
dose were mild or moderate musculoskeletal pain, occurring in 10%, and severe musculoskeletal pain
in 3% of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent
undesirable effects include urinary abnormalities predominantly mild or moderate dysuria.
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of
frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included nausea
and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, headache, cough, skin rash, chest pain,
generalised weakness, sore throat, constipation and unspecified pain.
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase (LDH),
alkaline phosphatase, serum uric acid and gamma-glutamyltransferase (GGT) occurred with filgrastim
in approximately 50%, 35%, 25%, and 10% of patients respectively, at recommended doses.
Transient decreases in blood pressure, not requiring clinical treatment, have been reported
occasionally.
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone
marrow transplantation (see section 5.1).
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been
reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone
marrow transplantation. The causal association with filgrastim has not been established.
Very rare events of cutaneous vasculitis have been reported in patients treated with filgrastim. The
mechanism of vasculitis in patients receiving filgrastim is unknown.
The occurrence of Sweet's syndrome (acute febrile dermatosis) has been reported occasionally.
However, since a significant percentage of these patients were suffering from leukaemia, a condition
known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been
established.
Exacerbation of rheumatoid arthritis has been observed in individual cases.
Pseudogout has been reported in patients with cancer treated with filgrastim.
Rare pulmonary undesirable effects including interstitial pneumonia, pulmonary oedema and
pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or adult
respiratory distress syndrome (ARDS) which may be fatal (see section 4.4).
Allergic Reactions: Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema,
dyspnoea and hypotension, occurring on initial or subsequent treatment, have been reported in patients
receiving filgrastim. Overall, reports were more common after IV administration. In some cases,
symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be
permanently discontinued in patients who experience a serious allergic reaction.
Isolated cases of sickle cells crises have been reported in patients with sickle cell disease (see section
4.4).
28
System organ class
Frequency
Undesirable effect
Metabolism and nutrition
disorders
Very common
Elevated alkaline phosphatase,
elevated LDH, elevated uric acid
Nervous system disorders
Common
Headache
Vascular disorders
Rare
Vascular disorder
Respiratory, thoracic and
mediastinal disorders
Common
Cough, sore throat
Very rare
Pulmonary infiltrates
Gastrointestinal disorders
Very common
Nausea/Vomiting
Common
Constipation, anorexia,
diarrhoea, mucositis
Hepatobiliary disorders
Very common
Elevated GGT
Skin and subcutaneous tissue
disorders
Common
Alopecia, skin rash
Very rare
Sweet's syndrome, cutaneous
vasculitis
Musculoskeletal and connective
tissue disorders
Very common
Chest pain, musculoskeletal pain
Very rare
Rheumatoid arthritis
exacerbation
Renal and urinary disorders
Very rare
Urinary abnormalities
General disorders and
administration site conditions
Common
Fatigue, generalised weakness
Uncommon
Unspecified pain
Very rare
Allergic reaction
In peripheral blood progenitor cell mobilisation in normal donors
The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal pain.
Leukocytosis (WBC > 50 x 10
9
/l) was observed in 41% of donors and transient thrombocytopenia
(platelets < 100 x 10
9
/l) following filgrastim and leukapheresis was observed in 35% of donors.
Transient, minor increases in alkaline phosphatase, LDH, SGOT (serum glutamic oxaloacetic
transaminase) and uric acid have been reported in normal donors receiving filgrastim; these were
without clinical sequelae.
Exacerbation of arthritic symptoms has been observed very rarely.
Symptoms suggestive of severe allergic reactions have been reported very rarely.
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture
have been reported in healthy donors and patients following administration of G-CSFs (see section
4.4).
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltration,
dyspnoea and hypoxia) have been reported in postmarketing experience (see section 4.4).
29
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Very common
Leukocytosis, thrombocytopenia
Uncommon
Spleen disorder
Metabolism and nutrition
disorders
Common
Elevated alkaline phosphatase,
elevated LDH
Uncommon
SGOT increased,
hyperuricaemia
Nervous system disorders
Very common
Headache
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
Uncommon
Rheumatoid arthritis
exacerbation
General disorders and
administration site conditions
Uncommon
Severe allergic reaction
In SCN patients
Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some their
frequencies tend to decrease with time.
The most frequent undesirable effects attributable to filgrastim were bone pain, and general
musculoskeletal pain.
Other undesirable effects seen include splenic enlargement, which may be progressive in a minority of
cases and thrombocytopenia. Headache and diarrhoea have been reported shortly after starting
filgrastim therapy, typically in less than 10% of patients. Anaemia and epistaxis have also been
reported.
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase
and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been
seen.
patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and
rash.
During long term use, cutaneous vasculitis has been reported in 2% of SCN patients. There have been
very few instances of proteinuria/haematuria.
30
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Very common
Anaemia, splenomegaly
Common
Thrombocytopenia
Uncommon
Spleen disorder
Metabolism and nutrition
disorders
Very common
Decreased glucose, elevated
alkaline phosphatase, elevated
LDH, hyperuricaemia
Nervous system disorders
Common
Headache
Respiratory, thoracic and
mediastinal disorders
Very common
Epistaxis
Gastrointestinal disorders
Common
Diarrhoea
Hepatobiliary disorders
Common
Hepatomegaly
Skin and subcutaneous tissue
disorders
Common
Alopecia, cutaneous vasculitis,
injection site pain, rash
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
Common
Osteoporosis
Renal and urinary disorders
Uncommon
Haematuria, proteinuria
In patients with HIV
In clinical studies, the only undesirable effects that were consistently considered to be related to
filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and
myalgia. The incidence of these events was similar to that reported in cancer patients.
Splenic enlargement was reported to be related to filgrastim therapy in < 3% of patients. In all cases
this was mild or moderate on physical examination and the clinical course was benign; no patients had
a diagnosis of hypersplenism and no patients underwent splenectomy. As splenic enlargement is a
common finding in patients with HIV infection and is present to varying degrees in most patients with
AIDS, the relationship to filgrastim treatment is unclear.
System organ class
Frequency
Undesirable effect
Blood and lymphatic system
disorders
Common
Spleen disorder
Musculoskeletal and connective
tissue disorders
Very common
Musculoskeletal pain
No case of overdose has been reported.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Colony stimulating factors, ATC code: L03AA02
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils
from the bone marrow. Ratiograstim containing r-metHuG-CSF (filgrastim) causes marked increases
in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some
SCN patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and
basophils relative to baseline; some of these patients may present with eosinophilia or basophilia prior
31
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.
Relative risk (95% CI) of GvHD and TRM following treatment with G-CSF after bone marrow
transplantation
Publication
Period of
study
N
Acute grade
II-IV GvHD
Chronic
GvHD
TRM
Meta-analysis
(2003)
1986-2001
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 bone marrow transplant during this period; some studies used
GM-CSF (granulocyte-macrophage–colony stimulating factor)
b
Analysis includes patients receiving bone marrow transplant during this period
Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normal
donors allows a collection of 4 x 10
6
CD34
+
cells/kg recipient body weight in the majority of the
donors after two leukaphereses. Normal donors are given a dose of a 10 μg/kg/day, administered
subcutaneously for 4 to 5 consecutive days.
Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic
neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a
reduction of infection and related events.
32
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled
dosing of antiviral and/or other myelosuppressive medicinal product. There is no evidence that
patients with HIV infection treated with filgrastim show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown
in vitro
stimulating properties on
human endothelial cells.
The efficacy and safety of Ratiograstim has been assessed in randomised, controlled phase III studies
in breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences
between Ratiograstim and the reference product with regard to duration of severe neutropenia and
incidence of febrile neutropenia.
5.2 Pharmacokinetic properties
Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the
pharmacokinetic profile of Ratiograstim was comparable to that of the reference product after
subcutaneous and intravenous administration.
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous
and intravenous administration. The serum elimination half-life of filgrastim is approximately
3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with filgrastim
over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation,
resulted in no evidence of drug accumulation and comparable elimination half-lives. There is a
positive linear correlation between the dose and the serum concentration of filgrastim, whether
administered intravenously or subcutaneously. Following subcutaneous administration of
recommended doses, serum concentrations were maintained above 10 ng/ml for 8 to 16 hours. The
volume of distribution in blood is approximately 150 ml/kg.
In cancer patients, the pharmacokinetic profile of Ratiograstim and the reference product was
comparable after single and repeated subcutaneous administration.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, genotoxicity and local tolerance.
Preclinical data from conventional studies of repeated dose toxicity revealed the expected
pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow,
extramedullary haematopoiesis and splenic enlargement.
No effect was observed on the fertility of male and female rats or gestation in rats. There is no
evidence from studies in rats and rabbits that filgrastim is teratogenic. An increased incidence of
embryo-loss has been observed in rabbits, but no malformation has been seen.
6.
6.1 List of excipients
Acetic acid, glacial
Sodium hydroxide
Sorbitol (E420)
Polysorbate 80
Water for injections
6.2 Incompatibilities
33
Ratiograstim should not be diluted with sodium chloride solution.
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
Diluted filgrastim may be adsorbed to glass and plastic materials except diluted, as mentioned in
section 6.6.
6.3 Shelf life
30 months.
After dilution: Chemical and physical in-use stability of the diluted solution for infusion has been
demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should
be used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
For storage conditions 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 with or without
safety device to prevent needle stick injury and re-use.
Packs containing 1, 5 or 10 pre-filled syringes with 0.8 ml solution for injection or infusion or
multipacks containing 10 (2 packs of 5) pre-filled syringes with 0.8 ml solution for injection or
infusion.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
If required, Ratiograstim may be diluted in glucose 50 mg/ml (5%) solution for infusion.
Dilution to a final concentration less than 0.2 MIU (2 μg) per ml is not recommended at any time.
The solution should be visually inspected prior to use. Only clear solutions without particles should be
used.
For patients treated with filgrastim diluted to concentrations below 1.5 MIU (15 μg) per ml, human
serum albumin (HSA) should be added to a final concentration of 2 mg/ml.
Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MIU (300 μg)
should be given with 0.2 ml of 200 mg/ml (20%) human albumin solution added.
When diluted in glucose 50 mg/ml (5%) solution for infusion, Ratiograstim is compatible with glass
and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene)
and polypropylene.
Ratiograstim does not contain any preservative. In view of the possible risk of microbial
contamination, Ratiograstim syringes are for single use only.
34
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
8.
EU/1/08/444/005
EU/1/08/444/006
EU/1/08/444/007
EU/1/08/444/008
EU/1/08/444/011
EU/1/08/444/012
9.
Date of first authorisation: 15 September 2008.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
35
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
36
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
SICOR Biotech UAB
Molėtų pl. 5
LT-08409 Vilnius
Lithuania
Name and address of the manufacturer responsible for batch release
Merckle Biotec GmbH
Dornierstraße 10
DE-89079 Ulm
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.1 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 5 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
37
ANNEX III
LABELLING AND PACKAGE LEAFLET
38
A. LABELLING
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton
1.
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in
0.5 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
1 pre-filled syringe without safety device containing 0.5 ml
1 pre-filled syringe with safety device containing 0.5 ml
5 pre-filled syringes without safety device containing 0.5 ml
5 pre-filled syringes with safety device containing 0.5 ml
10 pre-filled syringes without safety device containing 0.5 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
40
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/001 1 pre-filled syringe without safety device
EU/1/08/444/002 5 pre-filled syringes without safety device
EU/1/08/444/004 10 pre-filled syringes without safety device
EU/1/08/444/009 1 pre-filled syringe with safety device
EU/1/08/444/010 5 pre-filled syringes with safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ratiograstim 30 MIU/0.5 ml
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton
1.
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in
0.8 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
1 pre-filled syringe without safety device containing 0.8 ml
1 pre-filled syringe with safety device containing 0.8 ml
5 pre-filled syringes without safety device containing 0.8 ml
5 pre-filled syringes with safety device containing 0.8 ml
10 pre-filled syringes without safety device containing 0.8 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
42
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/005 1 pre-filled syringe without safety device
EU/1/08/444/006 5 pre-filled syringes without safety device
EU/1/08/444/008 10 pre-filled syringes without safety device
EU/1/08/444/011 1 pre-filled syringe with safety device
EU/1/08/444/012 5 pre-filled syringes with safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ratiograstim 48 MIU/0.8 ml
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Wrapper Label on Multipacks Wrapped in Transparent Foil - Including the Blue Box
1.
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in
0.5 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
10 pre-filled syringes without safety device containing 0.5 ml
Multipack comprising 2 packs, each containing 5 pre-filled syringes.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
44
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/003 2 x 5 pre-filled syringes without safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Wrapper Label on Multipacks Wrapped in Transparent Foil - Including the Blue Box
1.
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in
0.8 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
10 pre-filled syringes without safety device containing 0.8 ml
Multipack comprising 2 packs, each containing 5 pre-filled syringes.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
46
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/007 2 x 5 pre-filled syringes without safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
47
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Multipack Carton - Without the Blue Box
1.
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 30 million international units [MIU] (300 microgram) of filgrastim in
0.5 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
5 pre-filled syringes without safety device containing 0.5 ml
Component of a multipack comprising 2 packs, each containing 5 pre-filled syringes
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
48
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/003 2 x 5 pre-filled syringes without safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ratiograstim 30 MIU/0.5 ml
49
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Multipack Carton - Without the Blue Box
1.
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Filgrastim
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each pre-filled syringe contains 48 million international units [MIU] (480 microgram) of filgrastim in
0.8 ml (60 MIU/ml, 600 microgram/ml).
3.
LIST OF EXCIPIENTS
Excipients: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water for injections. Read
the package leaflet before use.
4.
Solution for injection or infusion
5 pre-filled syringes without safety device containing 0.8 ml
Component of a multipack comprising 2 packs, each containing 5 pre-filled syringes
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Subcutaneous use and intravenous use.
For single use only.
Please use as follows:
Box for the prescribed dose
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
50
8.
EXPIRY DATE
EXP
After dilution use within 24 hours.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
EU/1/08/444/007 2 x 5 pre-filled syringes without safety device
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ratiograstim 48 MIU/0.8 ml
51
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Pre-filled syringe
1.
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
Filgrastim
SC
IV
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.5 ml
6.
OTHER
52
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Pre-filled syringe
1.
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Filgrastim
SC
IV
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.8 ml
6.
OTHER
53
B. PACKAGE LEAFLET
54
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ratiograstim 30 MIU/0.5 ml solution for injection or infusion
Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Filgrastim
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Ratiograstim is and what it is used for
2. Before you use Ratiograstim
3. How to use Ratiograstim
4. Possible side effects
5.
How to store Ratiograstim
6.
Further information
1.
WHAT Ratiograstim
IS AND WHAT IT IS USED FOR
What Ratiograstim is
Ratiograstim contains the active substance filgrastim. Filgrastim is a protein produced by
biotechnology in bacteria called
Escherichia coli
. It belongs to a group of proteins called cytokines
and is very similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by
your own body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are made) to
produce more blood cells, especially certain types of white cells. White cells are important as they
help your body fight infection.
What Ratiograstim is used for
Your doctor has prescribed Ratiograstim for you to help your body make more white blood cells. Your
doctor will tell you why you are being treated with Ratiograstim. Ratiograstim is useful in several
different conditions which are:
-
chemotherapy,
-
bone marrow transplantation,
-
neutropenia in patients with HIV infection,
-
peripheral blood stem cell mobilisation.
2.
BEFORE YOU USE Ratiograstim
Do not use Ratiograstim
-
if you are allergic (hypersensitive) to filgrastim or to any of the other ingredients of
Ratiograstim.
Take special care with Ratiograstim
-
if you experience a cough, fever and difficulty breathing. It could be a consequence of a
pulmonary disorder (see section “4. POSSIBLE SIDE EFFECTS”).
-
if you have sickle cell disease; or
55
-
severe chronic neutropenia,
-
if you get left upper abdominal pain or pain at the tip of your shoulder.
It could be a consequence
of a spleen disorder (see section “4. POSSIBLE SIDE EFFECTS”).
You will need to have regular blood tests whilst being treated with Ratiograstim to count the number
of neutrophils and other white blood cells in your blood. This will tell your doctor how well the
treatment is working and will also indicate if treatment needs to be continued.
Using other medicines
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
Ask your doctor or pharmacist for advice before taking any medicine.
Ratiograstim has not been tested in pregnant women. It is important to tell your doctor if you are
pregnant, think you may be pregnant or plan to get pregnant, as the doctor may decide that you should
not use this medicine.
It is unknown whether filgrastim passes over to the breast milk. Therefore, your doctor may decide
that you should not use this medicine if you are breast-feeding.
Driving and using machines
If you experience fatigue, do not drive or use any tools or machines.
Important information about some of the ingredients of Ratiograstim
This medicine contains sorbitol (a type of sugar). If you have been told by your doctor that you have
an intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO USE Ratiograstim
Always use Ratiograstim exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is...
The amount of Ratiograstim you need will depend on the condition you are taking Ratiograstim for
and on your bodyweight. Your doctor will tell you when to stop using Ratiograstim. It is quite normal
to have a number of courses of Ratiograstim treatment.
Ratiograstim and chemotherapy
The usual dose is 0.5 million international units (MIU) per kilogram of bodyweight each day. For
example, if you weigh 60 kg your daily dose will be 30 million international units (MIU). Your
treatment will usually last for about 14 days. In some disease types however, longer treatment lasting
up to about one month may be required.
Ratiograstim and bone marrow transplantation
The usual starting dose is 1 million international units (MIU) per kilogram of bodyweight each day.
For example, if you weigh 60 kg your daily dose will be 60 million international units (MIU). You
will normally receive your first dose of Ratiograstim at least 24 hours after your chemotherapy but
within 24 hours of receiving your bone marrow transfusion. Your doctor will test your blood daily to
see how well the treatment is working and to find the dose that is best for you. The treatment will be
discontinued when white cells in your blood reach a certain number.
Ratiograstim and severe chronic neutropenia
The usual starting dose is between 0.5 million and 1.2 million international units (MIU) per kilogram
bodyweight each day in a single or divided dose. Your doctor will then test your blood to see how well
your treatment is working and to find the dose that is best for you. Long-term treatment with
Ratiograstim is required for neutropenia.
56
Ratiograstim and neutropenia in patients with HIV infection
The usual starting dose is between 0.1 and 0.4 million international units (MIU) per kilogram
bodyweight each day. Your doctor will test your blood at regular intervals to see how well the
treatment is working. Once the number of white cells in your blood have returned to normal it may be
possible to reduce the dose frequency to less than once per day. Your doctor will continue to test your
blood regularly and will recommend the best dose for you. Long term treatment with Ratiograstim
may be required to maintain a normal number of white cells in your blood.
Ratiograstim and peripheral blood stem cell mobilisation
If you are donating stem cells for yourself, the usual dose is 0.5 million to 1 million international units
(MIU) per kilogram bodyweight each day. Ratiograstim treatment will last for up to 2 weeks and in
exceptional cases longer. Your doctor will monitor your blood to determine the best time to collect the
stem cells.
If you are acting as a stem cell donor for another person, the usual dose is 1 million international units
(MIU) per kilogram bodyweight each day. Ratiograstim treatment will last for 4 to 5 days.
Method of administration
This medicine is given by injection, either through an intravenous infusion (drip) or into the tissue just
under the skin. This is known as a subcutaneous (SC) injection. If you are receiving this medicine by
subcutaneous injection, your doctor may suggest that you learn how to give yourself the injections.
Your doctor or nurse will give you instructions on how to do this. Do not attempt to self-administer
without this training. Some of the information you require is given at the end of this package leaflet,
but proper treatment of your disease requires close and constant co-operation with your doctor.
Each pre-filled syringe is for single use only.
If you use more Ratiograstim than you should
If you use more Ratiograstim than you should, contact your doctor or pharmacist as soon as possible.
If you forget to use Ratiograstim
Do not use a double dose to make up for a forgotten injection.
If you stop using Ratiograstim
Before you stop using Ratiograstim, talk to your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Ratiograstim can cause side effects, although not everybody gets them.
The following frequency conventions are used in the evaluation of side effects:
Very common: more than 1 user in 10
Common:
1 to 10 users in 100
Uncommon:
1 to 10 users in 1,000
Rare:
1 to 10 users in 10,000
Very rare:
less than 1 user in 10,000
Not known:
frequency cannot be estimated from the available data.
Allergic-type reactions to filgrastim, including skin rash, raised areas of the skin that itch and
anaphylaxis (weakness, drop in blood pressure, difficulty breathing and swelling of the face) have
been reported. If you think you are having this type of reaction, stop your Ratiograstim injection and
get medical help immediately.
57
Increased spleen size and very rare cases of spleen ruptures have been reported. Some cases of splenic
rupture were fatal.
It is important that you contact your
doctor immediately
if you experience
pain in the upper left side
of the abdomen or left shoulder pain
since this may relate to a problem with your spleen.
It is also very important that you call your doctor if you think you may have an infection. There are
many ways an infection may show itself. You should watch for a temperature of 37.8 °C or above,
chills or other signs of infection, such as a rash, sore throat, diarrhoea, ear-ache, difficult or painful
breathing or problems such as cough or wheezing. These symptoms could be signs of severe
pulmonary side effects, like pneumonia and respiratory distress syndrome in adults, which may be
fatal. If you have a fever or any of these symptoms, contact your doctor immediately and go straight to
your hospital.
If you have Sickle Cell Disease, make sure that you tell your doctor before you start taking
Ratiograstim. Sickle cell crisis has happened in some patients with Sickle Cell Disease who have been
given filgrastim.
As a very common side effect, filgrastim may cause bone and muscle pain. Ask your doctor which
medicine you can take to help with this.
You may experience the following additional side effects:
-
reduction in red blood cells which can make the skin pale and cause weakness or breathlessness,
reduction in blood platelets, which increases risk of bleeding or bruising, rise in white blood
cells
-
rejection of transplanted bone marrow (frequency unknown)
-
elevated levels of some liver or blood enzymes, high blood levels of uric acid, low blood levels
of glucose
-
headache
-
transient low blood pressure, vascular disorders (which can cause pain, redness and swelling in
the limbs)
-
nosebleed, cough, sore throat
-
cough, fever and difficulty breathing or coughing up blood (frequency unknown)
-
feeling sick, vomiting, constipation, diarrhoea, loss of appetite, mucositis (painful inflammation
and
ulceration
of the
mucous membranes
lining the
digestive tract)
-
pains or difficulties in passing urine (very rare), blood in the urine, protein in the urine
-
enlarged liver
-
inflammation of blood vessels, often with skin rash (very rare); the appearance of plum-
coloured, raised, painful lesions on the limbs (sometimes the face and neck) with fever (Sweet's
syndrome, very rare); hair loss; pain at the site of injection; rash
-
joint pain; chest pain; worsening of rheumatic conditions; loss of calcium from the bones; pain
and swelling of the joints, similar to gout (frequency unknown)
-
fatigue, generalised weakness, unspecified pain.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE Ratiograstim
Keep out of the reach and sight of children.
Do not use Ratiograstim after the expiry date which is stated on the outer carton and on the pre-filled
syringe after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
58
Do not use Ratiograstim if you notice it is cloudy or there are particles in it.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Ratiograstim contains
-
The active substance is filgrastim. Each ml of solution for injection or infusion contains
60 million international units [MIU] (600 µicrogram) of filgrastim.
Ratiograstim 30 MIU/0.5 ml: Each pre-filled syringe contains 30 million international units
[MIU] (300 microgram) of filgrastim in 0.5 ml solution.
Ratiograstim 48 MIU/0.8 ml: Each pre-filled syringe contains 48 million international units
[MIU] (480 microgram) of filgrastim in 0.8 ml solution.
-
The other ingredients are: Sodium hydroxide, glacial acetic acid, sorbitol, polysorbate 80, water
for injections.
You will find detailed information about the ingredient sorbitol (a sugar) in section 2. under the
heading “Important information about some of the ingredients of Ratiograstim”.
What Ratiograstim looks like and contents of the pack
Ratiograstim is a solution for injection or infusion in a pre-filled syringe with or without safety device.
Ratiograstim is a clear and colourless solution. Each pre-filled syringe contains 0.5 ml or 0.8 ml of
solution.
Ratiograstim are supplied in packs of 1, 5 or 10 pre-filled syringes or multipacks of 10 (2 packs of 5)
pre-filled syringes. Not all pack sizes may be marketed.
Marketing Authorisation Holder
ratiopharm GmbH
Graf-Arco-Straße 3
D-89079 Ulm
Germany
info@ratiopharm.de
Manufacturer
Merckle Biotec GmbH
Dornierstraße 10
D-89079 Ulm
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
ratiopharm Belgium S.A.
Tél/Tel: +32 2 761 10 11
Luxembourg/Luxemburg
ratiopharm S.A. Luxemburg
Tél/Tel: +35 2 40 37 27
България
ratiopharm GmbH, Германия
Teл: +49 731 402 02
Magyarország
ratiopharm Hungária Kft.
Tel: +36 1 273 2730
Česká republika
ratiopharm CZ s.r.o.
Tel: +420 2 510 21 122
Malta
ratiopharm GmbH, Il Ġermanja
Tel: +49 731 402 02
59
Danmark
ratiopharm A/S
Tlf: +45 45 46 06 60
Nederland
ratiopharm Nederland bv
Tel: +31 23 7070 840
Deutschland
ratiopharm GmbH
Tel: +49 731 402 02
Norge
ratiopharm AS
Tlf: +47 66 77 55 90
Eesti
ratiopharm Eesti büroo
Tel: +372 6838 006
Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
Tel: +43 1 97 007
Ελλάδα
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Polska
ratiopharm Polska Sp.z.o.o
Tel: +48 22 335 39 20
España
ratiopharm España, S.A.
Division ratiopharm direct
Tel: +34 91 567 29 70
Portugal
ratiopharm, Comércio e Indústria de Produtos
farmacêuticos Lda
Tel: +351 21 424 80 00
France
Laboratoire ratiopharm S.A.
Tél: +33 1 42 07 97 04
România
ratiopharm GmbH, Germania
Tel: +49 731 402 02
Ireland
ratiopharm UK Ltd, United Kingdom
Tel: +44 239 238 6330
Slovenija
ratiopharm GmbH, Nemčija
Tel: +49 731 402 02
Ísland
ratiopharm GmbH, Þýskaland
Sími: +49 731 402 02
Slovenská republika
ratiopharm Slovensko s.r.o.
Tel: +421 2 57 200 300
Italia
ratiopharm Italia s.r.l.
Division ratiopharm direct
Tel: +39 02 28 87 71
Suomi/Finland
ratiopharm Oy
Puh/Tel: +358 20 180 5900
Κύπρος
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Sverige
ratiopharm AB
Tel: +46 42 37 0740
Latvija
ratiopharm Latvijas pārstāvniecība
Tel: +371 67499110
United Kingdom
ratiopharm UK Ltd
Tel: +44 239 238 6330
Lietuva
ratiopharm atstovas Lietuvoje
Tel: + 370 5 212 3295
This leaflet was last approved in
60
INFORMATION FOR INJECTING YOURSELF
This section contains information on how to give yourself an injection of Ratiograstim. It is important
that you do not try to give yourself the injection unless you have received special training from your
doctor or nurse. If you are not sure about giving yourself the injection or you have any questions,
please ask your doctor or nurse for help.
Ratiograstim is supplied in pre-filled syringes either with or without safety device. The figures below
refer either to syringes with safety device (figures 2a, 2b, 7 and 8) or without (figures 1a and 1b). The
other figures (3, 4, 5, 6) apply to both syringes. Your doctor or pharmacist can tell you which
pre-filled syringe you have received. It is important that you dispose of the syringe without safety
device in a puncture-proof container.
How do I inject Ratiograstim myself?
You will need to give yourself the injection into the tissue just under the skin. This is known as a
subcutaneous injection. You will need to have your injections at about the same time every day.
Equipment that you need
To give yourself a subcutaneous injection you will need:
-
a pre-filled syringe of Ratiograstim,
-
alcohol wipes or similar,
-
a puncture-proof container (plastic container provided by the hospital or pharmacy) so you can
dispose of used syringes without safety device safely.
What should I do before I give myself a subcutaneous injection of Ratiograstim?
1.
Take your Ratiograstim pre-filled syringe out of the refrigerator.
3.
Check the expiry date on the pre-filled syringe label (EXP). Do not use it if the date has passed
the last day of the month shown.
4.
Check the appearance of Ratiograstim. It must be a clear and colourless liquid. If there are
particles in it, you must not use it.
5.
For a more comfortable injection, let the pre-filled syringe stand for 30 minutes to reach room
temperature or hold the pre-filled syringe gently in your hand for a few minutes. Do not warm
Ratiograstim in any other way (for example, do
not
warm it in a microwave or in hot water).
6.
Do
not
remove the cover from the syringe until you are ready to inject.
7.
Wash your hands thoroughly.
8.
Find a comfortable, well-lit place and put everything you need where you can reach them (the
Ratiograstim pre-filled syringe, alcohol wipes and the puncture-proof container).
How do I prepare my Ratiograstim injection?
Before you inject Ratiograstim you must do the following:
1.
Hold the syringe and gently take the cover from the needle without twisting. Pull straight as
shown in pictures 1 and 2 (see pictures 1a and 1b for syringes without safety device and
pictures 2a and 2b for syringes with safety device). Do not touch the needle or push the plunger.
61
2.
Try to self-inject at approximately the same time every day.
1a
1b
Without safety device
2a
2b
With safety device
2.
You may notice a small air bubble in the pre-filled syringe. If there are air bubbles present,
gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. With
the syringe pointing upwards, expel all air from the syringe by pushing the plunger upwards.
3.
The syringe has a scale on the syringe barrel. Push the plunger up to the number (ml) on the
syringe that matches the dose of Ratiograstim that your doctor prescribed.
4.
Check again to make sure the correct dose of Ratiograstim is in the syringe.
5.
You can now use the pre-filled syringe.
Where should I give my injection?
The most suitable places to inject yourself are:
-
the abdomen, except for the area around the navel (see picture 3).
3
4
If someone else is injecting you, they can also use the back of your arms (see picture 4).
It is better to change the injection site every day to avoid the risk of soreness at any one site.
62
-
the top of your thighs; and
How do I give my injection?
1.
Disinfect the injection site by using an alcohol wipe and pinch the skin between your thumb and
forefinger, without squeezing it (see picture 5).
2.
Put the needle fully into the skin as shown by your nurse or doctor (see picture 6).
3.
Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see
blood in the syringe, remove the needle and re-insert it in another place.
4.
Inject the liquid slowly and evenly, always keeping your skin pinched.
5.
Inject only the dose your doctor has told you.
6.
Syringe without safety device: After injecting the liquid, remove the needle and let go of your
skin.
Syringe with safety device: Remove the syringe from the injection site while keeping your
finger on the plunger (see picture 7). Orient the needle away from you and others and activate
the safety device by firmly pushing the plunger (see picture 8). You will hear a “click”, which
confirms activation of the safety device. The needle will be covered by the protective sleeve so
that you cannot prick yourself.
7.
Only use each syringe for one injection. Do not use any Ratiograstim that is left in the syringe.
5
6
7
8
With safety device
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
Syringes without safety device:
- Do not put the cover back on used needles.
- Put used syringes into the puncture-proof container and keep this container out of the reach and
sight of children.
- Dispose of the full puncture-proof container as instructed by your doctor, nurse or pharmacist.
- Never put the syringes that you have used into your normal household rubbish bin.
Syringes with safety device:
-
The safety device prevents needle stick injuries after use, so no special precautions for disposal
are required. Dispose of syringes with safety device as instructed by your doctor, nurse or
pharmacist.
63
THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE
PROFESSIONALS ONLY
Ratiograstim does not contain any preservative. In view of the possible risk of microbial
contamination, Ratiograstim syringes are for single use only.
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim.
Ratiograstim should not be diluted with sodium chloride solution. This medicinal product must not be
mixed with other medicinal products except those mentioned below. Diluted filgrastim may be
adsorbed to glass and plastic materials except diluted, as mentioned below.
If required, Ratiograstim may be diluted in glucose 50 mg/ml (5%) solution for infusion. Dilution to a
final concentration less than 0.2 MIU (2 μg) per ml is not recommended at any time. The solution
should be visually inspected prior to use. Only clear solutions without particles should be used. For
patients treated with filgrastim diluted to concentrations below 1.5 MIU (15 μg) per ml, human serum
albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: In a final injection
volume of 20 ml, total doses of filgrastim less than 30 MIU (300 μg) should be given with 0.2 ml of
200 mg/ml (20%) human albumin solution added. When diluted in glucose 50 mg/ml (5%) solution for
infusion, Ratiograstim is compatible with glass and a variety of plastics including PVC, polyolefin (a
co-polymer of polypropylene and polyethylene) and polypropylene.
After dilution: Chemical and physical in-use stability of the diluted solution for infusion has been
demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should
be used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless
dilution has taken place in controlled and validated aseptic conditions.
64
Source: European Medicines Agency
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