TEVAGRASTIM 48MUI/0.8ml 480mcg / 0.8ml injection / infusion solution medication leaflet

Tevagrastim 30 MIU/0.5 mL solution for injection/infusion

Tevagrastim 48 MIU/0.8 mL solution for injection/infusion

Each mL of solution for injection/infusion contains 60 million international units [MIU] (600 µg) offilgrastim.

Tevagrastim 30 MIU/0.5 mL solution for injection/infusion

Each pre-filled syringe contains 30 MIU (300 µg) of filgrastim in 0.5 mL solution for injection/infusion.

Tevagrastim 48 MIU/0.8 mL solution for injection/infusion

Each pre-filled syringe contains 48 MIU (480 µg) of filgrastim in 0.8 mL solution forinjection/infusion.

Filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) is produced in

Escherichia coli K802 by recombinant DNA technology.

Each mL of solution contains 50 mg of sorbitol.

For the full list of excipients, see section 6.1.

Solution for injection/infusion

Clear, colourless solution.

Tevagrastim 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.

Tevagrastim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).

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

Tevagrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to1.0 x 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 hasexperience in granulocyte colony-stimulating factor (G-CSF) treatment and haematology and has thenecessary diagnostic facilities. The mobilisation and apheresis procedures should be performed incollaboration with an oncology-haematology centre with acceptable experience in this field and wherethe 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 beadministered at least 24 hours after cytotoxic chemotherapy. In randomised clinical trials, asubcutaneous dose of 23 MIU (230 μg)/m2/day (4.0 to 8.4 μg/kg/day) was used.

Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and theneutrophil count has recovered to the normal range. Following established chemotherapy for solidtumours, lymphomas and lymphoid leukaemias, it is expected that the duration of treatment requiredto fulfil 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 for infusion given over 30 minutes (see section 6.6). The subcutaneous route ispreferred in most cases. There is some evidence from a study of single dose administration thatintravenous dosing may shorten the duration of effect. The clinical relevance of this finding tomultiple dose administration is not clear. The choice of route should depend on the individual clinicalcircumstance.

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.

The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy andat least 24 hours after bone 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 x 109/L for 3 consecutive days Reduce to 0.5 MIU (5 µg)/kg/day

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

If the ANC decreases to < 1.0 x 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 forinfusion (see section 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 MIU(10 μg)/kg/day for 5 to 7 consecutive days. Timing of leukapheresis: 1 or 2 leukapheresis on days 5and 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 MIU (5 μg)/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 x 109/L to > 5.0 x 109/L. Forpatients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In othercircumstances, additional leukapheresis are 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 for infusion (see section 6.6).

Filgrastim for PBPC mobilisation after myelosuppressive chemotherapy:

Filgrastim should be given by subcutaneous injection.

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

For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/dayfor 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 ifneeded in order to collect 4 x 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 MIU (12 μg)/kg/day as a single dose or in divided doses.

Idiopathic or cyclic neutropenia

The recommended starting dose is 0.5 MIU (5 μg)/kg/day as a single dose or in divided doses.

Filgrastim should be administered daily by subcutaneous injection until the neutrophil count hasreached and can be maintained at more than 1.5 x 109/L. When the response has been obtained, theminimal effective dose to maintain this level should be established. Long-term daily administration isrequired to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dosemay be doubled or halved depending upon the patient's response. Subsequently the dose may beindividually adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 109/Land 10 x 109/L. A faster schedule of dose escalation may be considered in patients presenting withsevere infections. In clinical trials, 97 % of patients who responded had a complete response at dosesof ≤ 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.

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 MIU (1 μg)/kg/day with titration up to a maximumof 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC> 2.0 x 109/L). In clinical studies, > 90 % of patients responded at these doses, achieving reversal ofneutropenia 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 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 MIU(300 μg)/day is recommended. Further dose adjustment may be necessary, as determined by thepatient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical studies, dosing with30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC > 2.0 x 109/L, withthe median dose frequency being 3 days per week. Long-term administration may be required tomaintain the ANC > 2.0 x 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 programme 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.

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 Tevagrastim in patients withclinically significant hypersensitivity. Do not administer filgrastim to patients with a history ofhypersensitivity to filgrastim or pegfilgrastim.

Pulmonary adverse effects

Pulmonary adverse reactions, 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 radiological signsof pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acuterespiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate treatmentgiven.

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 after

G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema andhaemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closelymonitored and receive standard symptomatic treatment, which may include a need for intensive care(see section 4.8).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and cases of splenic rupture have been reported 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 also be seen on some non-myeloid cells in vitro.

Myelodysplastic syndrome or chronic myeloid leukemia

The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome 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 x 109/l).

Leukocytosis

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

As with all therapeutic proteins, there is a potential for immunogenicity. Rates 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 also section 4.8.

Special warnings and precautions associated with co-morbidities

Special precautions in sickle cell trait and sickle cell disease

Sickle cell crisis, in some cases fatal, have been reported with the use of filgrastim in patients 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 maylead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (pleaserefer to the Summary of Product Characteristics of the specific chemotherapy agents used).

Effect of chemotherapy on erythrocytes and thrombocytes

Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due 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 tocause severe 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 x 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 mobilisation,may 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 yield of ≥ 2.0 x 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 x 109/L) following filgrastim administration andleukapheresis was observed in 35 % of subjects studied. Among these, two cases of platelets< 50 x 109/L were reported and attributed to the leukapheresis procedure.

If more than one leukapheresis is required, particular attention should be paid to donors with platelets< 100 x 109/L prior to leukapheresis; in general apheresis should not be performed if platelets< 75 x 109/L.

Leukapheresis should not be performed in donors who are anticoagulated or who have known 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 leukaemiain clinical trial patients with SCN treated with filgrastim. This observation has only been made inpatients with congenital neutropenia. MDS and leukaemias are natural complications of the diseaseand are of uncertain relation to filgrastim therapy. A subset of approximately 12 % of patients who hadnormal cytogenetic evaluations at baseline was 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 andproteinuria 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

ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Somepatients may respond very rapidly and with a considerable increase in neutrophil count to the initialdose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days offilgrastim administration. Thereafter, it is recommended that the ANC is measured at least twiceweekly for the first two weeks and subsequently once per week or once every other week duringmaintenance therapy. During intermittent dosing with 30 MIU (300 μg)/day of filgrastim, there can bewide 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 anyscheduled dosing with filgrastim.

Risk associated with increased doses of myelosuppressive medicinal products

Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due tomyelosuppressive medicinal products. As a result of the potential to receive higher doses or a greaternumber of these medicinal products with filgrastim therapy, the patient may be at higher risk ofdeveloping thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (seeabove).

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

Sorbitol

Tevagrastim contains sorbitol (E420). The additive effect of concomitantly given products containingsorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

For intravenous administration

Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unlessstrictly 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-threateningand should not be given in this population unless there is an overwhelming clinical need and noalternatives are available.

A detailed history of HFI symptoms has to be taken of each patient before giving this medicinalproduct.

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 numberof the administered product should be clearly recorded.

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, it 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 the breastfednewborns/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).

Filgrastim 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.

MedDRAsystem Adverse reactionsorgan class Very common Common Uncommon Rare(≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to (≥ 1/10,000 to< 1/100) < 1/1,000)

Infections Sepsisand Bronchitis

Infestations Upper respiratorytract infection

Urinary tractinfection

Blood and Thrombocytopenia Splenomegalya Leukocytosisa Splenic rupturealymphatic Anaemiae Haemoglobin Sickle cell anaemiasystem decreasede with crisisdisorders

Immune Hypersensitivity Anaphylacticsystem Drug reactiondisorders hypersensitivitya

Graft versus Host

Diseaseb

Metabolis Decreased appetitee Hyperuricaemia Blood glucosem and Blood lactate Blood uric acid decreasednutrition dehydrogenase increased Pseudogoutadisorders increased (Chondrocalcinosis

Pyrophosphate)

Fluid volumedisturbances

Psychiatic Insomniadiorders

Nervous Headachea Dizzinesssystem Hypoaesthesiadisorders Paraesthesia

Vascular Hypertension Veno-occlusive Capillary leakdisorders Hypotension diseased syndromea

Aortitis

Respirator Haemoptysis Acute respiratoryy, thoracic Dyspnoea distressand Cougha syndromeamediastinal Oropharyngeal Respiratorydisorders paina,e failurea

Epistaxis Pulmonaryoedemaa

Pulmonaryhaemorrhage

Interstitial lungdiseasea

Lung infiltrationa

Hypoxia

Gastro- Diarrhoeaa, e Oral painintestinal Vomitinga,e Constipationedisorders Nauseaa

Hepato- Hepatomegaly Aspartatebiliary Blood alkaline aminotransferasedisorders phosphatase increasedincreased Gamma-glutamyltransferaseincreased

Skin and Alopeciaa Rasha Rash Cutaneoussub- Erythema maculopapular vasculitisacutaneous Sweets syndrometissue (acute febriledisorders neutrophilicdermatosis)

Musculo- Musculoskeletal Muscle spasms Osteoporosis Bone densityskeletal painc decreasedand Exacerbation ofconnective rheumatoid arthritistissuedisorders

Renal and Dysuria Proteinuria Glomerulonephritisurinary Haematuria Urine abnormalitydisorders

General Fatiguea Chest paina Injection sitedisorders Mucosal Paina reactionand ad- inflammationa Astheniaaministratio Pyrexia Malaiseen site Oedema peripheraleconditions

Injury, Transfusionpoisoning reactioneandproceduralcomplicationsa See section c (Description of selected adverse reactions)b There have been reports of GvHD and fatalities in patients after allogeneic bone marrowtransplantation (see section c)c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain,musculoskeletal chest pain, neck paind Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or

PBPC mobilisatione Adverse events with higher incidence in filgrastim patients compared to placebo and associated withthe sequelae 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. Tevagrastim shouldbe permanently discontinued in patients who experience a serious allergic reaction.

Pulmonary adverse events

In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial 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 ofvasculitis in patients receiving filgrastim is unknown. During long term use cutaneous vasculitis hasbeen reported in 2% of SCN patients.

Leukocytosis

Leukocytosis (WBC > 50 x 109/l) was observed in 41% of normal donors and transientthrombocytopenia (platelets < 100 x 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 SCNreceiving 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

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

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

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophilsfrom the bone marrow. Tevagrastim containing r-metHuG-CSF (filgrastim) causes marked increasesin 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 andbasophils relative to baseline; some of these patients may present with eosinophilia or basophilia priorto treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophilsproduced in response to filgrastim show normal or enhanced function as demonstrated by tests ofchemotactic 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 duration 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 intoperipheral 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 PBPCsaccelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications andthe need for platelet transfusions.

Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapidhaematological 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 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 retrospectiveinternational 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 marrowtransplantation

Publication Period of N Acute grade Chronic TRMstudy II-IV GvHD GvHD

Meta-analysis 1986-2001a 1198 1.08 1.02 0.70(2003) (0.87, 1.33) (0.82, 1.26) (0.38, 1.31)

European 1992-2002b 1789 1.33 1.29 1.73retrospective (1.08, 1.64) (1.02, 1.61) (1.30, 2.32)study (2004)

International 1995-2000b 2110 1.11 1.10 1.26retrospective (0.86, 1.42) (0.86, 1.39) (0.95, 1.67)study (2006)aAnalysis includes studies involving bone marrow transplant during this period; some studies used

GM-CSF (granulocyte-macrophage colony-stimulating factor)bAnalysis includes patients receiving bone marrow transplant during this period

Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normaldonors allows a collection of ≥ 4 x 106 CD34+ cells/kg recipient body weight in the majority of thedonors after two leukapheresis. Normal donors are given a dose of a 10 μg/kg/day, administeredsubcutaneously for 4 to 5 consecutive days.

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.

The efficacy and safety of Tevagrastim has been assessed in randomised, controlled phase III studiesin breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differencesbetween Tevagrastim and the reference product with regard to duration of severe neutropenia andincidence of febrile neutropenia.

Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that thepharmacokinetic profile of Tevagrastim was comparable to that of the reference product aftersubcutaneous and intravenous 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.

In cancer patients, the pharmacokinetic profile of Tevagrastim and the reference product wascomparable after single and repeated subcutaneous administration.

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 leukocytes,myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. Thesechanges all reversed after discontinuation of treatment.

Effects of filgrastim on pre-natal development have been studied in rats and rabbits. Intravenous(80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis 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 reference product, comparablefindings plus increased foetal malformations were observed at 100 µg/kg/day, a maternally toxic dosewhich corresponded to a systemic exposure of approximately 50-90 times the exposures observed inpatients treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level forembryo-foetal toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure ofapproximately 3-5 times the exposures observed in patients treated with the clinical dose.

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

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

Acetic acid, glacial

Sodium hydroxide

Sorbitol (E420)

Polysorbate 80

Water for injections

Tevagrastim must not be diluted with sodium chloride solution.

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

Diluted filgrastim may be adsorbed to glass and plastic materials except diluted, as described insection 6.6.

30 months.

After dilution: Chemical and physical in-use stability of the diluted solution for infusion has beendemonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, the product shouldbe used immediately. 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 in a refrigerator (2 °C - 8 °C).

Within its shelf-life and for ambulatory use, the product may be removed from the refrigerator(2 °C - 8 °C) and stored at a temperature up to 25 °C for one single period of up to 4 days. If not usedwithin 4 days, the product may be returned to the refrigerator (2 °C - 8 °C) up to the expiry date.

Dispose of syringes if stored above 8 °C for more than 4 days.

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

Pre-filled syringe (type I glass) with injection needle (stainless steel), with or without a needle safetyguard.

Tevagrastim 30 MIU/0.5 mL solution for injection/infusion

Packs containing 1, 5 or 10 pre-filled syringes with 0.5 mL solution or multipacks containing 10 (2packs of 5) pre-filled syringes with 0.5 mL solution.

Tevagrastim 48 MIU/0.8 mL solution for injection/infusion

Packs containing 1, 5 or 10 pre-filled syringes with 0.8 mL solution or multipacks containing 10 (2packs of 5) pre-filled syringes with 0.8 mL solution.

Not all pack sizes may be marketed.

If required, Tevagrastim 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 beused.

For patients treated with filgrastim diluted to concentrations below 1.5 MIU (15 μg) 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 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, Tevagrastim is compatible with glassand a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene)and polypropylene.

Tevagrastim does not contain any preservative. In view of the possible risk of microbialcontamination, Tevagrastim syringes are for single use only.

Accidental exposure to freezing temperatures does not adversely affect the stability of Tevagrastim.

Using the pre-filled syringe with a needle safety guard

The needle safety guard covers the needle after injection to prevent needle stick injury. This does notaffect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose hasbeen given and the plunger cannot be depressed any further. While maintaining pressure on theplunger, remove the syringe from the patient. The needle safety guard will cover the needle whenreleasing the plunger.

Using the pre-filled syringe without a needle safety guard

Administer the dose as per standard protocol.

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

TEVA GmbH

Graf-Arco-Straße 389079 Ulm

Germany

Tevagrastim 30 MIU/0.5 mL solution for injection/infusion

EU/1/08/445/001

EU/1/08/445/002

EU/1/08/445/003

EU/1/08/445/004

EU/1/08/445/009

EU/1/08/445/010

EU/1/08/445/011

Tevagrastim 48 MIU/0.8 mL solution for injection/infusion

EU/1/08/445/005

EU/1/08/445/006

EU/1/08/445/007

EU/1/08/445/008

EU/1/08/445/012

EU/1/08/445/013

EU/1/08/445/014

Date of first authorisation: 15 September 2008.

Date of latest renewal: 19 July 2013.

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

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