Bio Sidus


Cosma Medical
Full Prescribing Info
ACTIVE INGREDIENT: Filgrastim (r-Met-hu-G-CSF)*.
Filgrastim is a highly purified, non-glycosylated, 175 amino acid protein. Filgrastim is produced in a laboratory strain of Escherichia coli bacteria which has been genetically modified by the insertion of the human gene codifying for the granulocyte colony stimulating factor.
Excipients/Inactive Ingredients: Sodium acetate buffer (pH=4.0), Polysorbate 80, Sorbitol, Water for injection.
1 vial of NEUTROMAX of 1.0 mL injection solution contains 30 million international units(=300 µg) of Filgrastim.
1 vial of NEUTROMAX of 1.6 mL injection solution contains 48 million international units (=480 µg) of Filgrastim.
FORMULA: See Table 1.

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Pharmacology: Pharmacodynamics: Human granulocyte colony stimulating factor is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow.
NEUTROMAX containing r-Met-hu-G-CSF, causes considerable increases in peripheral blood neutrophil counts within twenty four hours of administration, with minor increases in monocytes. Effects on neutrophil counts are dose-dependent. Neutrophils produced by the human body in response to NEUTROMAX show normal or even enhanced function, as demonstrated by tests of chemotactic and phagocytic function: Following discontinuation of NEUTROMAX therapy, circulating neutrophil counts decrease by 50% within 1 to 2 days, and returns to baseline levels within 1 to 7 days. Treatment with NEUTROMAX leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia frequently observed in patients undergoing cytotoxic chemotherapy. Patients treated with NEUTROMAX and cytotoxic chemotherapy require fewer and shorter hospitalization and decreased antibiotic usage compared to patients treated with cytotoxic chemotherapy alone.
Pharmacokinetics: There is a positive linear correlation between the dose and the serum concentration of r-Met-hu-G-CSF, whether administered intravenously or subcutaneously. After a single dose of Filgrastim in the range of 1.7 to 69.0 µg/kg (short i.v. infusion over 30 minutes), peak levels of r-Met-hu-G-CSF in the range of 5-1840 ng/mL were found.
Following s.c. administration of recommended doses, peak serum concentrations up to 118 ng/mL were maintained above 10 ng/mL for 8 to 16 hours. The volume of distribution in blood is approximately of 150 mL/kg.
Clearance of r-Met-hu-G-CSF has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration.The mean serum elimination half-life of r-Met-hu-G-CSF is approximately 3.5 hours, with a clearance rate of approximately 0.6 mL/min/kg. Continuous infusion with NEUTROMAX over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, showed no evidence of drug accumula­tion. Mean serum clearance half-life is also similar in this case.
Chemotherapy induced neutropenia: NEUTROMAX is indicated in patients with non-myeloid malignancy treated with established cytotoxic chemotherapy as it reduces the duration of neutropenia and the incidence of febrile neutropenia.
Patients receiving myeloablative chemotherapy followed by bone marrow transplantation: NEUTROMAX is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.
Peripheral blood progenitor cell mobilization (PBPC): NEUTROMAX is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis following either autologous or allogeneic stem cell transplantation.
Severe chronic neutropenia (SCN): Chronic administration of NEUTROMAX is indicated for reducing the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital, cyclic and idiopathic neutropenia.
Acute myelogenous leukemia (AML): NEUTROMAX is indicated to reduce the time required for neutrophil recovery and the duration of fever after induction or consolidation chemotherapy treatment of adults with acute myelogenous leukemia.
Dosage/Direction for Use
Chemotherapy induced neutropenia: The recommended dose of NEUTROMAX is 0.5 M I.U. (5 µg)/kg body-weight (corresponding to 16.6 µL of injection solution) once daily. A single vial of NEUTROMAX of 30 M.I.U. therefore provides the daily dose required by a patient of 60 kg body-weight.
In patients who received myeloablative-chemotherapy followed by bone marrow transplantation: The recommended starting dose of NEUTROMAX is 1.0 M I.U. (10 µg)/kg/day. Given as a 30 minutes or 24 hours intravenous infusion or 1.0 M I.U. (10 µg)/kg/day given by continuous 24 hours subcutaneous infusion. NEUTROMAX should be diluted in 20 mL of 5% glucose solution.
Once the neutrophil nadir has been passed, the daily dose of NEUTROMAX should be adjusted as follows: See Table 2.

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NEUTROMAX has been shown to be effective and well tolerated in this setting at doses up to 70 µg/kg/day.
Peripheral blood progenitor cell mobilization (PBPC) in autologous or allogeneic stem cell transplantation: The recommended dose of NEUTROMAX for PBPC mobilization is 1.0 M I.U. (10 µg)/kg/day subcutaneous injection or subcutaneous infusion once daily for 6-7 days with leukaphereses performed on days 5, 6 and 7.
NEUTROMAX should be maintained until the last leukapheresis. Leukapheresis should be continued until the cumulative CD34+ cell yield in the leukapheresis harvests is ≥5 x 106 cells/kg.
Severe chronic neutropenia (SCN):
The recommended starting dose for congenital neutropenia is 1.2 M I.U. (12 µg)/kg/day subcutaneous infection (single or divided doses). The recommended starting dose for idiopathic or cyclic neutropenia is 0.5 M I.U. (5 µg)/kg/day subcutaneous injection (single or divided doses). Chronic administration is required to maintain adequate ANC. Dose should be doubled or halved after 1-2 weeks depending on counts. The dose of NEUTROMAX may be adjusted every 1 to 2 weeks to maintain ANC between 2 to 10 x 109/L. Doses may need reducing if vasculitis occurs.
Acute myelogenous leukemia (AML): NEUTROMAX use as an adjunct to acute myelogenous leukemia induction and consolidation therapy: The recommended dose of NEUTROMAX is 0.5 M I.U. (5 µg)/kg/day. It should be started at least 24 hours after chemotherapy and be discontinued at least 24 hours before the next dose of chemotherapy.
Further information: Clinical trials with NEUTROMAX 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.
The safety and efficacy of NEUTROMAX have not been established in children.
Administration: NEUTROMAX may be administered as a subcutaneous injection or as a short intravenous infusion, diluted in 5% glucose solution, given over 30 minutes (see "Instructions for Dilution" as follows). The first dose of NEUTROMAX should not be administered during the 24 hours following cytotoxic chemotherapy but within 24 hours of bone marrow infusion. Daily dosing with NEUTROMAX should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. The required duration of treatment can be up to 14 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 the beginning of NEUTROMAX therapy. However, for a sustained therapeutic response, NEUTROMAX therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of NEUTROMAX therapy, prior to the time of the expected neutrophil nadir, is not recommended.
In patients treated with cytotoxic chemotherapy and autologous bone marrow transplantation, NEUTROMAX may be given as a subcutaneous or intravenous infusion diluted in 20-50 mL 5% glucose solution (see "Instructions for Dilution" as follows and also "Dosage.").
The first dose of NEUTROMAX should not be administered before 24 hours following cytotoxic chemotherapy but should be within 24 hours of bone marrow infusion. The efficacy and safety of NEUTROMAX given for periods exceeding 28 days in this setting and group of patients have not been established.
Instructions for Dilution: If required, NEUTROMAX may be diluted in a 5% glucose solution. Diluted NEUTROMAX may be adsorbed to glass and plastic materials. However, when diluted according to the following instructions, NEUTROMAX is compatible with glass and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.
If NEUTROMAX is diluted to a concentration below 1.5 M 1.U. (15 µg) per mL, human serum albumin (HSA) should be added to a final concentration of 2 mg/mL.
Example: In a final injection volume of 20 mL, total doses of NEUTROMAX less than 30 M I.U. (300 µg) should be given with 0.2 mL of 20% human albumin solution (Ph.Eur.) added.
Dilution to a final concentration less than 0.2 M I.U. (2 µg) per mL is not recommended at any time.
The effects of NEUTROMAX overdosage have not been established. Discontinuation of NEUTROMAX therapy usually results in a 50% decrease in circulating neutrophils within 1 or 2 days, with a return to normal level is in 1 to 7 days.
NEUTROMAX should not be administered in patients with known hypersensitivity to the active ingredient or its constituents. NEUTROMAX should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens. NEUTROMAX should not be administered to patients with severe congenital neutropenia (Kostmann's syndrome) with abnormal cytogenetics.
Special Precautions
Malignant Cell Growth: Granulocyte-colony stimulating factor can promote growth of myeloid cells and some­ non-myeloid cells in vitro. The safety and efficacy of NEUTROMAX administration in patients with myelodysplasia, acute myelogenous leukemia and chronic myelogenous leukemia have not been established. Therefore because of the possibility of tumor growth, NEUTROMAX is not indicated in any malignancy with myeloid-characteristics. Clinical trials have not yet established whether NEUTROMAX influences the progression of myelodysplastic syndrome to acute myeloblastic leukemia. Therefore, NEUTROMAX is not indicated in any pre-malignant myeloid condition.
Leukocytosis: White blood cells counts of 100 x 109/L or greater have been observed in less than 5% of patients receiving NEUTROMAX at doses above 0.3 M I.U./kg/day (3 µg/kg/day), although no other complication or side effects were reported. However, in view of the potential risks associated with severe leukocytosis, white blood cells counts should be performed at regular intervals during NEUTROMAX therapy. If leukocyte counts exceed 50 x 109/L after the expected nadir, NEUTROMAX should be discontinued immediately.
Risks associated with increased doses of chemotherapy: Special caution should be used when treating patients with high dose chemotherapy, because improved therapeutic responses have not been demonstrated and intensified doses of chemotherapeutic agents may lead to increased toxicities including cardiac, pulmonary, neurological and dermato­logical effects (please, refer to the prescribing information of the specific chemotherapy agents used).
Treatment with NEUTROMAX does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. Because of the potential risks that result from the use of higher doses of chemotherapy during NEUTROMAX therapy (e.g. full doses of the prescribed schedule), the patient may be at greater risk of thrombocytopenia and anaemia.
Regular monitoring of platelet count and hematocrit is recommended, especially when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
Other special precautions: Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with NEUTROMAX for more than 6 months.
Studies have not been performed with NEUTROMAX in patients with severe impairment of renal or hepatic functions and therefore its use in this patients group cannot be recommended. Likewise, the effects of NEUTROMAX in patients with substantially reduced myeloid progenitors have not been studied. NEUTROMAX acts primarily on neutrophil precursors to exert its effect in elevating neutrophil counts. Therefore, in patients with reduced precursors (such as those treated with extensive radiotherapy or chemotherapy), neutrophil response may be diminished.
Use In Pregnancy & Lactation
The safety of Filgrastim has not been established in pregnant women, though there is no evidence of teratogenic effects of NEUTROMAX from studies in rats and rabbits. An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been observed. In pregnancy, the possible risk of NEUTROMAX use to the fetus must be weighed against the expected therapeutic benefit. It is not known whether NEUTROMAX is excreted in human milk; consequently, it is not recommended for use in nursing women.
Side Effects
Administration of NEUTROMAX at the recommended dosage is frequently associated with musculoskeletal pain which is usually mild or moderate and generally controlled with analgesics. Its intensity is rarely severe.
Less frequent adverse events include urinary abnormalities (predominantly mild or moderate dysuria).
Transient decreases in blood pressure, not requiring clinical treatment, have been reported occasionally.
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase, alkaline phosphatase, serum uric acid, and gamma-glutamyl transpeptidase may frequently occur.
White blood cell counts of 100 x 109/L or greater have been observed in less than 5% of patients receiving NEUTROMAX at doses above 0.3 M I.U./kg/day (3 µg/kg/day), though no apparent complications were reported.
NEUTROMAX does not increase the incidence of clinical side effects associated with cytotoxic chemotherapy.
Frequency of side effects reported in patients treated with Filgrastim/chemotherapy and placebo/chemotherapy was similar and included nausea and vomiting, alopecia, diarrhea, fatigue, anorexia, mucositis, headache, cough, skin rash, chest pain, generalized weakness, sore throat, constipation and unspecified pain. Vascular disorders (e.g. veno-occlusive disease and fluid volume disturbances) have been reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone marrow transplantation, although the causal association with Filgrastim has not been established. Symptoms suggestive of allergic-type reactions have been reported in rare cases, approximately half of these were associated with the initial dose. Overall, reports were more common after i.v. administration. In some cases, rechallenge resulted in a recurrence of symptoms. Rare and sometimes fatal cases of interstitial pneumonia have been described with the use of NEUTROMAX after chemotherapy, particularly with regimens containing bleomycin, although no casual connection has been established.
Drug Interactions
The safety and efficacy of NEUTROMAX given on the same days as myelosuppressive cytotoxic chemotherapy has not been established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, its use is not recommended in the period from 24 hours before to 24 hours after chemotherapy. Possible Filgrastim interactions with other hematopoietic growth factors and cytokines have not yet been investigated in clinical trials (see Caution for Usage).
Caution For Usage
Incompatibilities: NEUTROMAX should not be diluted with saline solutions.
For compatibility of NEUTROMAX with plastic materials after dilution see Instructions for Dilution under Dosage & Administration.
NEUTROMAX should be stored in refrigerator between +2°C and +8°C.
NEUTROMAX vials are for single use only.
Shelf-Life: Two (2) years.
Diluted NEUTROMAX solutions should not be prepared more than 24 hours before administration and should be stored in refrigerator between +2°C and +8°C.
ATC Classification
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Inj (vial) 300 mcg/mL x 1's. 480 mcg/1.6 mL x 1's; (pre-filled syringe) 300 mcg/mL x 1's.
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