NIVESTIM 30MU/0.5ml 300mcg / 0.5ml injection / infusion solution medication leaflet

Nivestim 12 MU/0.2 ml solution for injection/infusion

Nivestim 30 MU/0.5 ml solution for injection/infusion

Nivestim 48 MU/0.5 ml solution for injection/infusion

Nivestim 12 MU/0.2 ml solution for injection/infusion

Each ml of solution for injection or infusion contains 60 million units [MU] (600 micrograms [mcg])of filgrastim*.

Each pre-filled syringe contains 12 million units (MU) (120 micrograms [mcg]) of filgrastim in 0.2 ml(0.6 mg/ml).

Nivestim 30 MU/0.5 ml solution for injection/infusion

Each ml of solution for injection or infusion contains 60 million units [MU] (600 micrograms [mcg])of filgrastim*.

Each pre-filled syringe contains 30 million units (MU) (300 micrograms [mcg]) of filgrastim in 0.5 ml(0.6 mg/ml).

Nivestim 48 MU/0.5 ml solution for injection/infusion

Each ml of solution for injection or infusion contains 96 million units [MU] (960 micrograms [mcg])of filgrastim*.

Each pre-filled syringe contains 48 million units (MU) (480 micrograms [mcg]) of filgrastim in 0.5 ml(0.96 mg/ml).

*recombinant methionyl granulocyte colony-stimulating factor G-CSF produced in Escherichia coli(BL21) by recombinant DNA technology.

Each ml of solution contains 50 mg of sorbitol (E420) (see section 4.4).

For the full list of excipients, see section 6.1.

Solution for injection/infusion (injection/infusion).

Clear, colourless solution.

Filgrastim is indicated for the reduction in the duration of neutropenia and the incidence of febrileneutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with theexception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in theduration of neutropenia in patients undergoing myeloablative therapy followed by bone marrowtransplantation considered to be at increased risk of prolonged severe neutropenia.

The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxicchemotherapy.

Filgrastim is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs).

In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with anabsolute neutrophil count (ANC) of ≤ 0.5 × 109/L, and a history of severe or recurrent infections, longterm administration of filgrastim is indicated to increase neutrophil counts and to reduce the incidenceand duration of infection-related events.

Filgrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to1.0 × 109/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infectionswhen other options to manage neutropenia are inappropriate.

Filgrastim therapy should only be given in collaboration with an oncology centre which has experiencein G-CSF treatment and haematology and has the necessary diagnostic facilities. The mobilisation andapheresis procedures should be performed in collaboration with an oncology-haematology centre withacceptable experience in this field and where the monitoring of haematopoietic progenitor cells can becorrectly performed.

Established cytotoxic chemotherapy

The recommended dose of filgrastim is 0.5 MU (5 mcg)/kg/day. The first dose of filgrastim should beadministered at least 24 hours after cytotoxic chemotherapy. In randomised clinical trials, asubcutaneous dose of 230 µg/m2/day (4.0 to 8.4 mcg/kg/day) was used.

Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and theneutrophil count has recovered to the normal range. Following established chemotherapy for solidtumours, lymphomas, and lymphoid leukaemia, it is expected that the duration of treatment required tofulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acutemyeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending onthe type, dose and schedule of cytotoxic chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen1 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 neutrophilcount has recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to thetime of the expected neutrophil nadir, is not recommended.

Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in5% glucose solution given over 30 minutes (see section 6.6). The subcutaneous route is preferred inmost cases. There is some evidence from a study of single dose administration that intravenous dosingmay shorten the duration of effect. The clinical relevance of this finding to multiple doseadministration is not clear. The choice of route should depend on the individual clinical circumstance.

In patients treated with myeloablative therapy followed by bone marrow transplantation

The recommended starting dose of filgrastim is 1.0 MU (10 mcg)/kg/day. The first dose of filgrastimshould be administered at least 24 hours following cytotoxic chemotherapy and at least 24 hours afterbone marrow infusion.

Once the neutrophil nadir has been passed, the daily dose of filgrastim should be titrated against theneutrophil response as follows:

Neutrophil count Filgrastim dose adjustment> 1.0 × 109/L for 3 consecutive days Reduce to 0.5 MU (5 mcg)/kg/day

Then, if ANC remains > 1.0 × 109/L for 3 more Discontinue filgrastimconsecutive days

If the ANC decreases to < 1.0 × 109/L during the treatment period the dose of filgrastim should bere-escalated according to the above steps

ANC = absolute neutrophil count

Filgrastim may be given as a 30 minute or 24 hour intravenous infusion or given by continuous24 hour subcutaneous infusion. Filgrastim should be diluted in 20 ml of 5% glucose solution (seesection 6.6).

For the mobilisation of PBPCs in patients undergoing myelosuppressive or myeloablative therapyfollowed by autologous PBPC transplantation

The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MU(10 mcg)/kg/day for 5 to 7 consecutive days. Timing of leukapheresis: one or two leukapheresis ondays 5 and 6 are often sufficient. In other circumstances, additional leukapheresis may be necessary.

Filgrastim dosing should be maintained until the last leukapheresis.

The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is0.5 MU (5 mcg)/kg/day from the first day after completion of chemotherapy until the expectedneutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresisshould be performed during the period when the ANC rises from < 0.5 × 109/L to > 5.0 × 109/L. Forpatients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In othercircumstances, additional leukapheresis is recommended.

Filgrastim for PBPC mobilisation when used alone:

Filgrastim may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. Forinfusions filgrastim should be diluted in 20 ml of 5% glucose solution (see section 6.6).

Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy:

Filgrastim should be given by subcutaneous injection.

For the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation

For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MU(10 mcg)/kg/day for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continueduntil day 6 if needed in order to collect 4 × 106 CD34+ cells/kg recipient bodyweight.

Filgrastim should be given by subcutaneous injection.

In patients with severe chronic neutropenia (SCN)

Congenital neutropenia: The recommended starting dose is 1.2 MU (12 mcg)/kg/day as a single doseor in divided doses.

Idiopathic or cyclic neutropenia: The recommended starting dose is 0.5 MU (5 mcg)/kg/day as a singledose or in divided doses.

Dose adjustment: Filgrastim should be administered daily by subcutaneous injection until theneutrophil count has reached and can be maintained at more than 1.5 × 109/L. When the response hasbeen obtained the minimal effective dose to maintain this level should be established. Long term dailyadministration 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 thedose may be individually adjusted every 1 to 2 weeks to maintain the average neutrophil countbetween 1.5 × 109/L and 10 × 109/L. A faster schedule of dose escalation may be considered inpatients presenting with severe infections. In clinical trials, 97% of patients who responded had acomplete response at doses ≤ 24 mcg/kg/day. The long-term safety of filgrastim administration above24 mcg/kg/day in patients with SCN has not been established.

Congenital, idiopathic or cyclic neutropenia: Filgrastim should be given by subcutaneous injection.

In patients with HIV infection

For reversal of neutropenia:

The recommended starting dose of filgrastim is 0.1 MU (1 mcg)/kg/day with titration up to amaximum of 0.4 MU (4 mcg)/kg/day until a normal neutrophil count is reached and can be maintained(ANC > 2.0 × 109/L). In clinical studies, > 90% of patients responded at these doses, achievingreversal of neutropenia in a median of 2 days.

In a small number of patients (< 10%), doses up to 1.0 MU (10 mcg)/kg/day were required to achievereversal of neutropenia.

For maintaining normal neutrophil counts:

When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normalneutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MU(300 mcg)/day is recommended. Further dose adjustment may be necessary, as determined by thepatient's ANC, to maintain the neutrophil count at > 2.0 × 109/L. In clinical studies, dosing with30 MU (300 mcg)/day on 1 to 7 days per week was required to maintain the ANC > 2.0 × 109/L, withthe median dose frequency being 3 days per week. Long term administration may be required tomaintain the ANC > 2.0 × 109/L.

Reversal of neutropenia or maintaining normal neutrophil counts: filgrastim should be given bysubcutaneous injection.

Clinical trials with filgrastim have included a small number of elderly patients but special studies havenot been performed in this group and therefore specific dosage recommendations cannot be made.

Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that itexhibits 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 program were under 18 years of age. Theefficacy of treatment was clear for this age group, which included most patients with congenitalneutropenia. There were no differences in the safety profiles for paediatric patients treated for SCN.

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim aresimilar in both adults and children receiving cytotoxic chemotherapy.

The dosage recommendations in paediatric patients are the same as those in adults receivingmyelosuppressive cytotoxic chemotherapy.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Special warnings and precautions across indications

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment havebeen reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients withclinically significant hypersensitivity. Do not administer filgrastim to patients with a history ofhypersensitivity to filgrastim or pegfilgrastim.

Pulmonary adverse effects

Pulmonary adverse effects, in particular interstitial lung disease, have been reported after G-CSFadministration. 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 radiologicalsigns of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs ofacute respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriatetreatment given.

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally,events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim andpegfilgrastim. Urinalysis monitoring is recommended.

Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported aftergranulocyte-colony stimulating factor administration, and is characterised by hypotension,hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillaryleak syndrome should be closely monitored and receive standard symptomatic treatment, which mayinclude a need for intensive care (see section 4.8).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported inpatients and normal donors following administration of filgrastim. Some cases of splenic rupture werefatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). Adiagnosis of splenic rupture should be considered in donors and/or patients reporting left upperabdominal or shoulder tip pain. Dose reductions of filgrastim have been noted to slow or stop theprogression of splenic enlargement in patients with severe chronic neutropenia, and in 3% of patients asplenectomy was required.

Malignant cell growth

Granulocyte colony-stimulating factor can promote growth of myeloid cells in vitro and similar effectsmay be seen on some non-myeloid cells in vitro.

Myelodysplastic syndrome or chronic myeloid leukaemia

The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome, orchronic myelogenous leukaemia have not been established. Filgrastim is not indicated for use in theseconditions. Particular care should be taken to distinguish the diagnosis of blast transformation ofchronic myeloid leukaemia from acute myeloid leukaemia.

Acute myeloid leukaemia

In view of limited safety and efficacy data in patients with secondary AML, filgrastim should beadministered with caution. The safety and efficacy of filgrastim administration in de novo AMLpatients aged < 55 years with good cytogenetics (t(8;21), t(15;17), and inv(16)) have not beenestablished.

Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should bemonitored closely, especially during the first few weeks of filgrastim therapy. Consideration should begiven to temporary discontinuation or dose reduction of filgrastim in patients with severe chronicneutropenia who develop thrombocytopenia (platelet count < 100 × 109/L).

Leucocytosis

White blood cell counts of 100 × 109/L or greater have been observed in less than 5% of cancerpatients receiving filgrastim at doses above 0.3 MU/kg/day (3 mcg/kg/day). No undesirable effectsdirectly attributable to this degree of leucocytosis have been reported. However, in view of thepotential risks associated with severe leucocytosis, a white blood cell count should be performed atregular intervals during filgrastim therapy. If leucocyte counts exceed 50 × 109/L after the expectednadir, filgrastim should be discontinued immediately. When administered for PBPC mobilisation,filgrastim should be discontinued or its dosage should be reduced if the leucocyte counts rise to> 70 × 109/L.

As with all therapeutic proteins, there is a potential for immunogenicity. Rate of generation ofantibodies against filgrastim is generally low. Binding antibodies do occur as expected with allbiologics; however, they have not been associated with neutralising activity at present.

Aortitis

Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. Thesymptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatorymarkers (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 section 4.8).

Special warnings and precautions associated with co-morbidities

Special precautions in sickle cell trait and sickle cell disease

Sickle cell crises, in some cases fatal, have been reported with the use of filgrastim in patients withsickle cell trait or sickle cell disease. Physicians should use caution when prescribing filgrastim inpatients with sickle cell trait or sickle cell disease.

Osteoporosis

Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseaseswho undergo continuous therapy with filgrastim for more than 6 months.

Special precautions in cancer patients

Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond establisheddosage regimens.

Risks associated with increased doses of chemotherapy

Special caution should be used when treating patients with high dose chemotherapy, because improvedtumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may leadto increased toxicities including cardiac, pulmonary, neurologic, and dermatologic effects (please referto the prescribing information of the specific chemotherapy agents used).

Effect of chemotherapy on erythrocytes and thrombocytes

Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due tomyelosuppressive 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 andanaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care shouldbe taken when administering single or combination chemotherapeutic agents which are known to causesevere thrombocytopenia.

The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration ofthrombocytopenia following myelosuppressive or myeloablative chemotherapy.

Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients

In the post-marketing observational study setting, myelodysplastic syndrome (MDS) and acutemyeloid leukaemia (AML) have been associated with the use of pegfilgrastim, an alternative G-CSFmedicine, in conjunction with chemotherapy and/or radiotherapy in breast and lung cancer patients. Asimilar association between filgrastim and MDS/AML has not been observed. Nonetheless, patientswith breast cancer and patients with lung cancer should be monitored for signs and symptoms of

MDS/AML.

Other special precautions

The effects of filgrastim in patients with substantially reduced myeloid progenitors have not beenstudied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophilcounts. Therefore, in patients with reduced precursors neutrophil response may be diminished (such asthose treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration bytumour).

Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have beenreported 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-CSFafter allogeneic bone marrow transplantation (see sections 4.8 and 5.1).

Increased haematopoietic activity of the bone marrow in response to growth factor therapy has beenassociated with transient abnormal bone scans. This should be considered when interpretingbone-imaging results.

Special precautions in patients undergoing PBPC mobilisation

Mobilisation

There are no prospectively randomised comparisons of the two recommended mobilisation methods(filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patientpopulation. 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 difficultto recommend an optimum method. The choice of mobilisation method should be considered inrelation 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 sufficientmobilisation of PBPC to achieve the recommended minimum yield (≥ 2.0 × 106 CD34+ cells/kg) oracceleration of platelet recovery, to the same degree.

Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool, and mayadversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU), andcarboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisationmay reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNUtogether with filgrastim has been shown to be effective for progenitor mobilisation. When a PBPCtransplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in thetreatment course of the patient. Particular attention should be paid to the number of progenitorsmobilised in such patients before the administration of high-dose chemotherapy. If yields areinadequate, as measured by the criteria above, alternative forms of treatment, not requiring progenitorsupport should be considered.

Assessment of progenitor cell yields

In assessing the number of progenitor cells harvested in patients treated with filgrastim, particularattention 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 ofnumbers 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 ofplatelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.

The recommendation of a minimum yields of ≥ 2.0 × 106 CD34+ cells/kg is based on publishedexperience resulting in adequate haematologic reconstitution. Yields in excess of this appear tocorrelate with more rapid recovery, those below with slower recovery.

Special precautions in normal donors undergoing PBPC mobilisation

Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only beconsidered for the purposes of allogeneic stem cell transplantation.

PBPC mobilisation should be considered only in donors who meet normal clinical and laboratoryeligibility criteria for stem cell donation with special attention to haematological values and infectiousdisease.

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 andleukapheresis 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 defectsin haemostasis.

Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indicesreturn to normal.

Special precautions in recipients of allogeneic PBPCs mobilised with filgrastim

Current data indicate that immunological interactions between the allogeneic PBPC graft and therecipient may be associated with an increased risk of acute and chronic GvHD when compared withbone marrow transplantation.

Special precautions in SCN patients

Filgrastim should not be administered to patients with severe congenital neutropenia who developleukaemia or have evidence of leukaemic evolution.

Blood cell counts

Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors,which require close monitoring of cell counts.

Transformation to leukaemia or myelodysplastic syndrome

Special care should be taken in the diagnosis of SCNs to distinguish them from other haematopoieticdisorders such as aplastic anaemia, myelodysplasia, and myeloid leukaemia. Complete blood cellcounts with differential and platelet counts, and an evaluation of bone marrow morphology andkaryotype should be performed prior to treatment.

There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia inclinical trial patients with SCN treated with filgrastim. This observation has only been made in patientswith congenital neutropenia. MDS and leukaemias are natural complications of the disease and are ofuncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had normalcytogenetic evaluations at baseline were subsequently found to have abnormalities, includingmonosomy 7, on routine repeat evaluation. It is currently unclear whether long-term treatment ofpatients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemictransformation. It is recommended to perform morphologic and cytogenetic bone marrowexaminations in patients at regular intervals (approximately every 12 months).

Other special precautions

Causes of transient neutropenia, such as viral infections should be excluded.

Haematuria was common and proteinuria occurred in a small number of patients. Regular urinalysisshould be performed to monitor these events.

The safety and efficacy in neonates and patients with autoimmune neutropenia have not beenestablished.

Special precautions in patients with HIV infection

Blood cell counts

Absolute neutrophil count (ANC) should be monitored closely, especially during the first few weeksof filgrastim therapy. Some patients may respond very rapidly and with a considerable increase inneutrophil count to the initial dose of filgrastim. It is recommended that the ANC is measured daily forthe first 2-3 days of filgrastim administration. Thereafter, it is recommended that the ANC is measuredat least twice per week for the first two weeks and subsequently once per week or once every otherweek during maintenance therapy. During intermittent dosing with 30 MU (300 mcg)/day offilgrastim, there can be wide fluctuations in the patient's ANC over time. In order to determine apatient's trough or nadir ANC, it is recommended that blood samples are taken for ANC measurementimmediately 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 tomyelosuppressive medications. As a result of the potential to receive higher doses or a greater numberof these medications with filgrastim therapy, the patient may be at higher risk of developingthrombocytopenia 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 Mycobacteriumavium complex or malignancies such as lymphoma. In patients with known bone marrow infiltratinginfections or malignancy, consider appropriate therapy for treatment of the underlying condition, inaddition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim onneutropenia due to bone marrow infiltrating infection or malignancy have not been well established.

All patients

Nivestim contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) must not begiven this medicine unless strictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructoseintolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may belife-threatening and should be contraindicated in this population unless there is an overwhelmingclinical need and no alternatives are available.

A detailed history with regard to HFI symptoms has to be taken of each patient prior to being giventhis medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per 0.6 mg/ml or 0.96 mg/ml dose, that is tosay essentially ‘sodium-free’.

The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxicchemotherapy have not been definitively established. In view of the sensitivity of rapidly dividingmyeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommendedin the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a smallnumber of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severityof neutropenia may be exacerbated.

Possible interactions with other haematopoietic growth factors and cytokines have not yet beeninvestigated in clinical trials.

Since lithium promotes the release of neutrophils, lithium is likely to potentiate the effect of filgrastim.

Although this interaction has not been formally investigated, there is no evidence that such aninteraction is harmful.

There are no or limited amount of data from the use of filgrastim in pregnant women. Studies inanimals have shown reproductive toxicity. An increased incidence of embryo loss has been observedin rabbits at high multiples of the clinical exposure and in the presence of maternal toxicity (seesection 5.3). There are reports in the literature where the transplacental passage of filgrastim inpregnant women has been demonstrated.

Filgrastim is not recommended during pregnancy.

It is unknown whether filgrastim/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from filgrastim therapy taking into account the benefit of breast-feeding forthe 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).

Nivestim may have a minor influence on the ability to drive and use machines. Dizziness may occurfollowing the administration of filgrastim (see section 4.8).

The most serious adverse reactions that may occur during filgrastim treatment include: anaphylacticreaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillaryleak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome orleukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheralblood 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 includesbone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletalchest pain, neck pain), anaemia, vomiting, and nausea. In clinical trials in cancer patientsmusculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients.

b. Tabulated summary of adverse reactions

The data in the table below describe adverse reactions reported from clinical trials and spontaneousreporting. Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

MedDRA Adverse reactionssystem organ Very common Common Uncommon Rareclass (≥ 1/10) (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to< 1/10) < 1/100) < 1/1,000)

Infections and Sepsisinfestations Bronchitis

Upperrespiratorytract infection

Urinary tractinfection

Blood and Thrombocytopenia Splenomegalya Leucocytosisa Splenic rupturealymphatic

Anaemiae Haemoglobin Sickle cell anaemiasystemdecreasede with crisisdisorders

Extramedullaryhaematopoiesis

Immune system Hypersensitivity Anaphylactic reactiondisorders Drughypersensitivitya

Graft versushost diseaseb

MedDRA Adverse reactionssystem organ Very common Common Uncommon Rareclass (≥ 1/10) (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to< 1/10) < 1/100) < 1/1,000)

Metabolism Decreased Hyperuricaemia Blood glucoseand nutrition appetitee Blood uric acid decreaseddisorders Blood lactate increased Pseudogoutadehydrogenase (Chondrocalcinosisincreased Pyrophosphate)

Fluid volumedisturbances

Psychiatric Insomniadisorders

Nervous system Headachea Dizzinessdisorders Hypoaesthesia

Paraesthesia

Vascular Hypertension Veno-occlusive Capillary leakdisorders Hypotension diseased syndromea

Aortitis

Respiratory, Haemoptysis Acutethoracic and respiratory

Dyspnoeamediastinal distressdisorders Cougha syndromea

Oropharyngeal Respiratorypaina,e failurea

Epistaxis Pulmonaryoedemaa

Pulmonaryhaemorrhage

Interstitial lungdiseasea

Lunginfiltrationa

Hypoxia

Gastrointestinal Diarrhoeaa,e Oral paindisorders Vomitinga,e Constipatione

Nauseaa

Hepatobiliary Hepatomegaly Aspartatedisorders Blood alkaline aminotransferasephosphatase increasedincreased Gamma-glutamyltransferaseincreased

MedDRA Adverse reactionssystem organ Very common Common Uncommon Rareclass (≥ 1/10) (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to< 1/10) < 1/100) < 1/1,000)

Skin and Alopeciaa Rasha Rash maculo- Cutaneous vasculitisasubcutaneous

Erythema papular Sweets syndrometissue disorders (acute febrileneutrophilicdermatosis)

Musculoskeletal Musculoskeletal Muscle Osteoporosis Bone densityand connective painc spasms decreasedtissue disorders Exacerbation ofrheumatoid arthritis

Renal and Dysuria Proteinuria Glomerulonephritisurinary

Haematuria Urine abnormalitydisorders

General Fatiguea Chest paina Injection sitedisorders and Mucosal Paina reactionadministrationinflammationasite conditions Astheniaa

Pyrexia Malaisee

Oedemaperipherale

Injury, Transfusionpoisoning and reactioneproceduralcomplicationsa See section c (Description of selected adverse reactions).b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (seesection c).c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletalchest pain, neck pain.d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPCmobilisation.e Adverse events with higher incidence in filgrastim patients compared to placebo and associated with thesequelae of the underlying malignancy or cytotoxic chemotherapy.

c. Description of selected adverse reactions

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea andhypotension occurring on initial or subsequent treatment have been reported in clinical studies and inpost-marketing experience. Overall, reports were more common after IV administration. In somecases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should bepermanently discontinued in patients who experience a serious allergic reaction.

Pulmonary adverse events

In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lungdisease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome ofrespiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see section4.4).

Splenomegaly and splenic rupture

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim.

Some cases of splenic rupture were fatal (see section 4.4).

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 multiplechemotherapy medications or undergoing apheresis (see section 4.4).

Cutaneous vasculitis

Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitisin patients receiving filgrastim is unknown. During long-term use cutaneous vasculitis has beenreported in 2% of SCN patients.

Leucocytosis

Leucocytosis (WBC > 50 × 109/L) was observed in 41% of normal donors and transientthrombocytopenia (platelets < 100 × 109/L) following filgrastim and leukapheresis was observed in35% of donors (see section 4.4).

Sweets syndrome

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patientstreated with filgrastim.

Pseudogout (chondrocalcinosis pyrophosphate)

Pseudogout (chondrocalcinosis pyrophosphate) has been reported in patients with cancer treated withfilgrastim.

GvHD

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bonemarrow transplantation (see sections 4.4 and 5.1).

d. Paediatric population

Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim aresimilar in both adults and children receiving cytotoxic chemotherapy suggesting no age-relateddifferences in the pharmacokinetics of filgrastim. The only consistently reported adverse event wasmusculoskeletal pain‚ which is no different from the experience in the adult population.

There is insufficient data to further evaluate filgrastim use in paediatric subjects.

e. Other special populations

Geriatric use

No overall differences in safety or effectiveness were observed between subjects over 65 years of agecompared to younger adult (> 18 years of age) subjects receiving cytotoxic chemotherapy and clinicalexperience 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 filgrastimindications.

Paediatric SCN patients

Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severechronic neutropenia receiving chronic treatment with filgrastim.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The effects of filgrastim overdosage have not been established.

Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophilswithin 1 to 2 days, with a return to normal levels in 1 to 7 days.

Pharmacotherapeutic group: Immunostimulants colony stimulating factors, ATC code: L03AA02

Nivestim is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophilsfrom the bone marrow. Nivestim containing r-metHuG-CSF (filgrastim) causes marked increases inperipheral blood neutrophil counts within twenty four hours, with minor increases in monocytes. Insome SCN patients filgrastim can also induce a minor increase in the number of circulating eosinophilsand basophils relative to baseline; some of these patients may present with eosinophilia or basophiliaalready prior to treatment. Elevations of neutrophil counts are dose dependent at recommended doses.

Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated bytests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulatingneutrophil 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 theincidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastimsignificantly reduces the durations of febrile neutropenia, antibiotic use and hospitalisation afterinduction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bonemarrow transplantation. The incidence of fever and documented infections were not reduced in eithersetting. The duration of fever was not reduced in patients undergoing myeloablative therapy followedby bone marrow transplantation.

Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells intothe peripheral blood. These autologous PBPCs may be harvested and infused after high dose cytotoxictherapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerateshaematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need forplatelet transfusions.

Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapidhaematological recovery, leading to a significant decrease in time to unsupported platelet recoverywhen compared with allogeneic bone marrow transplantation.

One retrospective European study evaluating the use of G-CSF after allogeneic bone marrowtransplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatmentrelated 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 theresults of nine prospective randomised trials, 8 retrospective studies and 1 case-controlled study, didnot 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

Period of Acute Grade II Chronic

Publication N TRM

Study - IV GvHD GvHD1.08 1.02 0.70

Meta-Analysis (2003) 1986 2001a 1198(0.87, 1.33) (0.82, 1.26) (0.38, 1.31)

European Retrospective 1992  1.33 1.29 1.73b 1789

Study (2004) 2002 (1.08, 1.64) (1.02, 1.61) (1.30, 2.32)

International

Retrospective Study 1995  1.11 1.10 1.26b 21102000 (0.86, 1.42) (0.86, 1.39) (0.95, 1.67)(2006)a Analysis includes studies involving BM transplant during this period; some studies used GM-CSF.b Analysis includes patients receiving BM transplant during this period.

Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPCtransplantation

In normal donors, a 10 mcg/kg/day dose administered subcutaneously for 4 to 5 consecutive daysallows a collection of ≥ 4 × 106 CD34+ cells/kg recipient body weight in the majority of the donorsafter two leukapheresis.

Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathicneutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and areduction of infection and related events.

Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduleddosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with

HIV infection treated with filgrastim show an increase in HIV replication.

As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties onhuman endothelial cells.

A randomised, open-label, single-dose, comparator-controlled, two-way crossover study in 46 healthyvolunteers showed that the pharmacokinetic profile of Nivestim was comparable to that of thereference product after subcutaneous and intravenous administration. Another randomised,double-blind, multiple-dose, comparator-controlled, two-way crossover study in 50 healthy volunteersshowed that the pharmacokinetic profile of Nivestim was comparable to that of the reference productafter subcutaneous administration.

Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneousand intravenous administration. The serum elimination half-life of filgrastim is approximately3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with filgrastimover 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 apositive linear correlation between the dose and the serum concentration of filgrastim, whetheradministered intravenously or subcutaneously. Following subcutaneous administration ofrecommended doses, serum concentrations were maintained above 10 ng/ml for 8 to 16 hours. Thevolume of distribution in blood is approximately 150 ml/kg.

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealedchanges attributable to the expected pharmacological actions including increases in leucocytes,myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. Thesechanges all reversed after discontinuation of treatment.

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous(80 mcg/kg/day) administration of filgrastim to rabbits during the period of organogenesis wasmaternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean livelitter size and foetal weight were observed.

Based on reported data for another filgrastim product similar to the originator, comparable findingsplus increased foetal malformations were observed at 100 mcg/kg/day, a maternally toxic dose whichcorresponded to a systemic exposure of approximately 50-90 times the exposures observed in patientstreated with the clinical dose of 5 mcg/kg/day. The no observed adverse effect level for embryo-foetaltoxicity in this study was 10 mcg/kg/day, which corresponded to a systemic exposure of approximately3-5 times the exposures observed in patients treated with the clinical dose.

In pregnant rats, no maternal or foetal toxicity was observed at doses up to 575 mcg/kg/day. Offspringof rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in externaldifferentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate(100 mcg/kg/day).

Filgrastim had no observed effect on the fertility of male or female rats.

Acetic acid, glacial

Sodium hydroxide

Sorbitol (E420)

Polysorbate 80

Water for injections

Nivestim should not be diluted with sodium chloride solutions.

Diluted filgrastim may be adsorbed to glass and plastic materials unless it is diluted in 5% glucosesolution (see section 6.6).

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Pre-filled syringe30 months.

Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for24 hours at 2°C to 8°C. From a microbiological point of view, the product should be usedimmediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unlessdilution has taken place in controlled and validated aseptic conditions.

Store and transport refrigerated (2°C to 8°C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

Accidental exposure to freezing temperatures for up to 24 hours does not affect the stability of

Nivestim. The frozen pre-filled syringes can be thawed and then refrigerated for future use. If exposurehas been greater than 24 hours or frozen more than once, then Nivestim should NOT be used.

Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product fromthe refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15days. At the end of this period, the product should not be put back in the refrigerator and should bedisposed of.

For storage conditions after dilution of the medicinal product, see section 6.3.

Nivestim 12 MU/0.2 ml solution for injection/infusion

Pre-filled syringe (type I glass), with injection needle (stainless steel) with a needle guard, containing0.2 ml solution for injection/infusion.

Nivestim 30 MU/0.5 ml solution for injection/infusion, Nivestim 48 MU/0.5 ml solution forinjection/infusion

Pre-filled syringe (type I glass), with injection needle (stainless steel) with a needle guard, containing0.5 ml solution for injection/infusion.

Each pre-filled syringe is affixed with a needle closed by a needle cover that contains epoxyprene, aderivative of natural rubber latex which may come into contact with the needle.

Pack sizes of 1, 5, 8 or 10 pre-filled syringes.

Not all pack sizes may be marketed.

If required, Nivestim may be diluted in 5% glucose solution.

Dilution to a final concentration less than 0.2 MU (2 mcg) per ml is not recommended at any time.

The solution should be visually inspected prior to use. Only clear solutions without particles should beused.

For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 mcg) per ml, humanserum albumin (HSA) should be added to a final concentration of 2 mg/ml.

Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 mcg)should be given with 0.2 ml of 20% human albumin solution Ph. Eur. added.

Nivestim contains no preservative. In view of the possible risk of microbial contamination, Nivestimsyringes are for single use only.

When diluted in 5% glucose solution, filgrastim is compatible with glass and a variety of plasticsincluding PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/10/631/001

EU/1/10/631/002

EU/1/10/631/003

EU/1/10/631/004

EU/1/10/631/005

EU/1/10/631/006

EU/1/10/631/007

EU/1/10/631/008

EU/1/10/631/009

EU/1/10/631/010

EU/1/10/631/011

EU/1/10/631/012

Date of first authorisation: 08 June 2010

Date of latest renewal: 27 May 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.