Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Ratiopharm GmbH, Graf-Arco-Straße 3, 89079 Ulm, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with filgrastim. Permanently discontinue Ratiograstim in patients with clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of hypersensitivity to filgrastim or pegfilgrastim
Pulmonary adverse reactions, in particular interstitial lung disease, have been reported after G-CSF administration. Patients with a recent history of lung infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment given.
Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Capillary leak syndrome which can be life threatening if treatment is delayed, has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see section 4.8).
Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported in patients and normal donors following administration of filgrastim. Some cases of splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper abdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop the progression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients a splenectomy was required.
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. 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.
Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic neutropenia who develop thrombocytopenia (platelet count < 100 × 109/l).
White blood cell counts of 100 × 109/L or greater have been observed in less than 5% of cancer patients receiving filgrastim at doses above 0.3 MIU/kg/day (3 μg/kg/day). No undesirable effects directly attributable to this degree of leukocytosis have been reported. However, in view of the potential risks associated with severe leukocytosis, a white blood cell count should be performed at regular intervals during filgrastim therapy. If leukocyte counts exceed 50 × 109/L after the expected nadir, filgrastim should be discontinued immediately. However, during the period of administration of filgrastim for PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to >70 × 109/L.
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against filgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present.
Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.
Sickle cell crisis, in some cases fatal, have been reported with the use of filgrastim in patients with sickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim in patients with sickle cell trait or sickle cell disease.
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.
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
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.
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration by tumour).
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported occasionally in patients undergoing high dose chemotherapy followed by transplantation.
There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see section 4.8 and 5.1).
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient abnormal bone scans This should be considered when interpreting bone-imaging results.
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.
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient mobilisation of PBPC to achieve the recommended minimum yield (≥2.0 × 106 CD34+ cells/kg) or acceleration of platelet recovery to the same degree.
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation, may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU together with filgrastim has been shown to be effective for progenitor mobilisation. When a PBPC transplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in the treatment course of the patient. Particular attention should be paid to the number of progenitors mobilised in such patients before the administration of high-dose chemotherapy. If yields are inadequate, as measured by the criteria above, alternative forms of treatment not requiring progenitor support should be considered.
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular attention should be paid to the method of quantitation. The results of flow cytometric analysis of CD34+ cell numbers vary depending on the precise methodology used and recommendations of numbers based on studies in other laboratories need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.
The recommendation of a minimum yield of ≥2.0 × 106 CD34+ cells/kg is based on published experience resulting in adequate haematologic reconstitution. Yields in excess of this appear to correlate with more rapid recovery, those below with slower recovery.
Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory eligibility criteria for stem cell donation with special attention to haematological values and infectious disease.
The safety and efficacy of filgrastim have not been assessed in normal donors <16 years or >60 years.
Transient thrombocytopenia (platelets <100 × 109/L) following filgrastim administration and leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets <50 × 109/L were reported and attributed to the leukapheresis procedure.
If more than one leukapheresis is required, particular attention should be paid to donors with platelets <100 × 109/L prior to leukapheresis; in general apheresis should not be performed if platelets <75 × 109/L.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices return to normal.
Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The significance of these changes is unknown. Nevertheless, a risk of promotion of a malignant myeloid clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
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.
Filgrastim should not be administered to patients with severe congenital neutropenia who develop leukaemia or have evidence of leukaemic evolution.
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, which require close monitoring of cell counts
Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoietic disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell counts with differential and platelet counts and an evaluation of bone marrow morphology and karyotype should be performed prior to treatment.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in clinical trial patients with SCN treated with filgrastim. This observation has only been made in patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had normal cytogenetic evaluations at baseline was subsequently found to have abnormalities, including monosomy 7, on routine repeat evaluation. It is currently unclear whether long-term treatment of patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic transformation. It is recommended to perform morphologic and cytogenetic bone marrow examinations in patients at regular intervals (approximately every 12 months).
Causes of transient neutropenia such as viral infections should be excluded.
Haematuria was common andproteinuria occurred in a small number of patients. Regular urinalysis should be performed to monitor these events.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
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.
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).
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.
Ratiograstim contains sorbitol (E420). The additive effect of concomitantly given products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless strictly necessary. Infants and young children (below 2 years of age) may not yet be diagnosed with HFI. Medicinal products (containing sorbitol/fructose) given intravenously may be life-threatening and should not be given in this population unless there is an overwhelming clinical need and no alternatives are available.
A detailed history of HFI symptoms has to be taken of each patient before giving this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially ‘sodium-free’.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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 or limited amount of data from the use of filgrastim in pregnant women. Studies in animals have shown reproductive toxicity. An increased incidence of embryo-loss has been observed in rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity (see section 5.3). There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated.
Filgrastim is not recommended during pregnancy.
It is unknown whether filgrastim/metabolites are excreted in human breast milk. A risk to the breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from filgrastim therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Filgrastim did not affect reproductive performance or fertility in male or female rats (see section 5.3).
Filgrastim may have a minor influence on the ability to drive and use machines. Dizziness may occur following the administration of filgrastim (see section 4.8).
The most serious adverse reactions that may occur during filgrastim treatment include: anaphylactic reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.
The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain), anaemia, vomiting, and nausea. In clinical trials in cancer patients musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients.
The data in the tables below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| MedDRA system organ class | Very common (≥1/10) | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) | Rare (≥1/10,000 to <1/1,000) | Very rare (<1/10,000) |
|---|---|---|---|---|---|
| Infections and Infestations | Sepsis, Bronchitis, Upper respiratory tract infection, Urinary tract infection | ||||
| Blood and lymphatic system disorders | Thrombocytopenia, Anaemiae | Splenomegalya, Haemoglobin decreasede | Leukocytosisa | Splenic rupturea, Sickle cell anaemia with crisisa | |
| Immune system disorders | Hypersensitivity, Drug hypersensitivitya, Graft versus Host Diseaseb | Anaphylactic reaction | |||
| Metabolism and nutrition disorders | Decreased appetitee, Blood lactate dehydrogenase increased | Hyperuricaemia, Blood uric acid increased | Blood glucose decreased, Pseudogouta (Chondrocal cinosis Pyrophosphate), Fluid volume disturbances | ||
| Psychiatic diorders | Insomnia | ||||
| Nervous system disorders | Headachea | Dizziness, Hypoaesthesia, Paraesthesia | |||
| Vascular disorders | Hypertension, Hypotension | Venoocclusive diseased | Capillary leak syndromea, Aortitis | ||
| Respiratory, thoracic and mediastinal disorders | Haemoptysis, Dyspnoea, Cougha Oropharyngeal paina,e, Epistaxis | Acute respiratory distress syndromea, Respiratory failurea, Pulmonary oedemaa, Pulmonary haemorrhage, Interstitial lung diseasea, Lung infiltrationa, Hypoxia | |||
| Gastrointestinal disorders | Diarrhoeaa,e, Vomitinga,e, Nauseaa | Oral pain, Constipatione | |||
| Hepatobiliary disorders | Hepatomegaly, Blood alkaline phosphatase increased | Aspartate aminotransferase increased, Gammaglutamyl transferase increased | |||
| Skin and subcutaneous tissue disorders | Alopeciaa | Rasha, Erythema | Rash maculopapular | Cutaneous vasculitisa, Sweets syndrome (acute febrile neutrophilic dermatosis) | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal painc | Muscle spasms | Osteoporosis | Bone density decreased, Exacerbation of rheumatoid arthritis | |
| Renal and urinary disorders | Dysuria, Haematuria | Proteinuria | Glomerulon ephritis, Urine abnormality | ||
| General disorders and administration site conditions | Fatiguea, Mucosal inflammationa, Pyrexia | Chest paina, Paina, Astheniaa, Malaisee, Oedema peripherale | Injection site reaction | ||
| Injury, poisoning and procedural complications | Transfusion reactione |
a See section c (Description of selected adverse reactions)
b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section c)
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain
d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC mobilization
e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy
Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in post marketing experience. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be permanently discontinued in patients who experience a serious allergic reaction.
In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung disease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome of respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see section 4.4).
Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. Some cases of splenic rupture were fatal (see section 4.4).
Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis (see section 4.4).
Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitis in patients receiving filgrastim is unknown. During long term use cutaneous vasculitis has been reported in 2% of SCN patients.
Leukocytosis (WBC >50 × 109/l) was observed in 41% of normal donors and transient thrombocytopenia (platelets <100 × 109/l) following filgrastim and leukapheresis was observed in 35% of donors (see section 4.4).
Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients treated with filgrastim.
Pseudogout (chondrocalcinosis pyrophosphate) has been reported in patients with cancer treated with filgrastim.
There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see section 4.4 and 5.1).
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy suggesting no age-related differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.
There is insufficient data to further evaluate filgrastim use in paediatric subjects.
No overall differences in safety or effectiveness were observed between subjects over 65 years of age compared to younger adult (>18 years of age) subjects receiving cytotoxic chemotherapy and clinical experience has not identified differences in the responses between elderly and younger adult patients.
There is insufficient data to evaluate filgrastim use in geriatric subjects for other approved filgrastim indications.
Cases of decreased bone density and osteoporosis have been reported in paediatric patients with SCN receiving chronic treatment with filgrastim.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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.
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