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  • Tevagrastim
    / Teva


    Active Ingredient
    Filgrastim 0.6 mg/ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Pre-filled Syringe

    1 X 30 MIU (300 mcg) / 0.5 ml

    partial basket chart 18959 20675

    Pre-filled Syringe

    1 X 48 MIU (480 mcg) / 0.8 ml

    partial basket chart 18961 20678

    Pre-filled Syringe

    5 X 30 MIU / 0.5 ml

    partial basket chart 18960 20676

    Pre-filled Syringe

    5 X 48 MIU / 0.8 ml

    partial basket chart 18962 20677

    Related information


    Dosage

    Special requirements: Filgrastim therapy should only be given in collaboration with an oncology centre which has experience in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the necessary diagnostic facilities. The mobilisation and apheresis procedures should be performed in collaboration with an oncology-haematology centre with acceptable experience in this field and where the monitoring of haematopoietic progenitor cells can be correctly performed.
    Established cytotoxic chemotherapy: The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/ml (5%) solution for infusion given over 30 minutes. The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose administration that intravenous dosing may shorten the duration of effect. The clinical relevance of this finding to multiple dose administration is not clear. The choice of route should depend on the individual clinical circumstance. In randomised clinical trials, a subcutaneous dose of 23 MIU (230 μg)/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 the neutrophil count has recovered to the normal range. Following established chemotherapy for solid tumours, lymphomas and lymphoid leukaemias, it is expected that the duration of treatment required to fulfill these criteria will be up to 14 days. Following induction and consolidation treatment for acute myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on the type, dose and schedule of cytotoxic chemotherapy used. In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of filgrastim therapy prior to the time of the expected neutrophil nadir is not recommended.
    In patients treated with myeloablative therapy followed by bone marrow transplantation: The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or 24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous infusion. Filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion (see section 6.6 for instructions on dilution). The first dose of filgrastim should not be administered less than 24 hours following cytotoxic chemotherapy and within 24 hours of bone marrow infusion. Once the neutrophil nadir has been passed the daily dose of filgrastim should be titrated against the neutrophil response. See prescribing information for full details.
    For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation: The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU (10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion. Timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Filgrastim dosing should be maintained until the last leukapheresis. The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 0.5 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis should be performed during the period when the ANC rises from <0.5 x 109/l to >5.0 x 10 9 /l. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended.
    For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell transplantation: For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/day subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order to collect 4 x 10 6 CD34+cells/kg recipient bodyweight.
    In patients with severe chronic neutropenia (SCN) Congenital neutropenia: The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in divided doses.
    Idiopathic or cyclic neutropenia: The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously as a single dose or in divided doses.
    Dose adjustment: Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 x 109/l. When the response has been obtained, the minimal effective dose to maintain this level should be established. Long-term daily administration is required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose may be doubled or halved depending upon the patient’s response. Subsequently the dose may be individually adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 109/l and 10 x 109/l. A faster schedule of dose escalation may be considered in patients presenting with severe infections. In clinical trials, 97%of patients who responded had a complete response at doses of 2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU (24 μg)/kg/day in patients with SCN has not been established.
    In patients with HIV infection
    For reversal of neutropenia: The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous injection with titration up to a maximum of 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC >2.0 x109/l).In clinical studies, > 90%of patients responded at these doses, achieving reversal of neutropenia in a median of 2 days. In a small number of patients (<10%), doses up to 1.0 MIU (10 μg)/kg/day were required to achieve reversal of neutropenia.
    For maintaining normal neutrophil counts: When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU (300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary, as determined by the patient’s ANC, to maintain the neutrophil count at >2.0 x 109/l. In clinical studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC >2.0 x 109/l, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC >2.0 x 109 /l.
    Special populations
    Elderly patients: Clinical trials with filgrastim have included a small number of elderly patients but special studies have not been performed in this group and therefore specific dosage recommendations cannot be made.
    Patients with renal or hepatic impairment: Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. Dose adjustment is not required in these circumstances.
    Paediatric use in the SCN and cancer settings: Sixty-five percent of the patients studied in the SCN trial programme were under 18 years of age. The efficacy of treatment was clear for this age group, which included most patients with congenital neutropenia. There were no differences in the safety profiles for paediatric patients treated for severe chronic neutropenia. Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy. The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy.
    See prescribing information for full details.


    Indications

    For the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
    For the mobilisation of peripheral blood progenitor cells in normal donors (allogeneic PBPC).
    Long term administration is indicated in patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of 0.5 x 109/l, and a history of severe or recurrent infections, to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
    For the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.


    Special Precautions

    Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
    Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman’s syndrome) with abnormal cytogenetics.
    Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF.
    Special precautions in patients with acute myeloid leukaemia:
    Malignant cell growth: Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may also be seen on some non-myeloid cells in vitro. The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for use in these conditions. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia. In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be administered with caution. The safety and efficacy of filgrastim administration in de novo AML patients aged <55 years with good cytogenetics [t(8;21),t(15;17),and inv(16)]have not been established.
    Other special precautions: Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with filgrastim for more than 6 months. Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment given in these cases. Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. There have been reports of graft versus host disease (GvHD) and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation. In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, dyspnoea and hypoxia) have been reported very rarely in postmarketing experience. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with filgrastim should be considered and appropriate medical care given.
    This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially ‘sodium-free’.
    See prescribing information for full details.


    Side Effects

    In cancer patients: In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended dose were mild or moderate musculoskeletal pain, occurring in 10%, and severe musculoskeletal pain in 3% of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent undesirable effects include urinary abnormalities predominantly mild or moderate dysuria.
    In peripheral blood progenitor cell mobilisation in normal donors: The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal pain.
    Leukocytosis (WBC > 50 x 109 /L) was observed in 41% of donors and transient
    thrombocytopenia (platelets < 100 x 109 /L) following filgrastim and leukapheresis was observed in 35% of donors.
    In SCN patients: Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some their frequencies tend to decrease with time. The most frequent undesirable effects attributable to filgrastim were bone pain, and general musculoskeletal pain.
    In patients with HIV:  In clinical studies, the only undesirable effects that were consistently considered to be related to filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and myalgia. The incidence of these events was similar to that reported in cancer patients.
    See prescribing information for full details.


    Drug interactions

    The safety and efficacy of filgrastim given on the same day as myelosuppressivecytotoxic chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small number of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severity of neutropenia may be exacerbated. Possible interactions with other haematopoietic growth factors and cytokines have not yet been investigated in clinical trials. Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. Although this interaction has not been formally investigated, there is no evidence that such an interaction is harmful.


    Pregnancy and Lactation

    Pregnancy: There are no adequate data from the use of filgrastim in pregnant women. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Filgrastim should not be used during pregnancy unless clearly necessary.
    Breastfeeding: It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with filgrastim should be made taking into account the benefit of breast-feeding to the child and the benefit of filgrastim therapy to the woman.


    Overdose

    No case of overdose has been reported.
    Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels in 1 to 7 days.


    Important notes

    Storage: Store this medicine in the refrigerator (2°C – 8°C).
    Patient can store the medicine out of refrigerator below 25°C, for up to 5 days, without exceeding the expiry date. Once removed from the refrigerator, the medicine should be used within 5 days or be disposed of. The medicine should not be returned to the refrigerator.


    Manufacturer
    Teva Pharmaceutical Industries Ltd, Israel
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