FILGRASTIM (LEUCOGEN) is a human granulocyte colony stimulating factor (r-metHuG-CSF), which is produced by recombinant DNA technology in the Centro de Immunologia Molecular. FILGRASTIM (LEUCOGEN) is a 175 amino acid nonglycosylated protein, with a molecular weight of 18,000 D. FILGRASTIM (LEUCOGEN) is produced by Escherichia coli (E. coli) bacteria into which has been inserted the human granulocyte colony stimulating factor gene.
Composition: Each 1 mL vial contains: Filgrastim 300 mcg, sorbitol 50 mg, polysorbate 80 40 mcg, sodium acetate 123 mcg, acetic acid 500 mcg and water for injection 1 mL.
Pharmacology: Colony-stimulating factors are glycoprotein which acts on haematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment, and some end-cell functional activation. Endogenous G-CSF is a lineage specific colony-stimulating factor which is produced by monocytes, fibroblasts, and endothelial cells. FILGRASTIM (LEUCOGEN) contains r-metHuG-CSF, which regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing and the increased expression of some functions associated with cell surface antigens). G-CSF Is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of haematopoietic cell types other than the neutrophil lineage.
Cancer Patients Receiving Myelosuppressive Chemotherapy: Neutropenia and infection are major dose-limiting side effects of chemotherapy. The risk of initial infection and subsequent complications is directly related to the depth and duration of neutropenia. The magnitude of neutropenia is dependent on the intensity of the chemotherapy regimen. Filgrastim has been shown to be safe and effective in accelerating the recovery of neutrophil counts following a variety of chemotherapy regimens. The benefits of therapy were shown to be prevention of infection as manifested by febrile neutropenia, decreased hospitalization, and decreased antibiotic usage. No difference in survival or disease progression was demonstrated.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: Essentially, all patients with Acute Myeloid Leukemia receiving induction therapy, and most such patients receiving intensive, post remission consolidation therapy, develop fevers requiring hospitalization and intravenous antibiotics until neutrophil recovery occurs. Treatment with Filgrastim significantly reduced the median time to Absolute Neutrophil Counts (ANC) recovery and the median duration of fever, antibiotic use and hospitalization following induction chemotherapy. There are no reports of Filgrastim effects related with complete remission rate, disease-free survival, time to progression, or overall survival.
Cancer Patients Receiving Bone Marrow Transplant: The major complications of high-dose chemotherapy supported by autologous bone marrow transplant (BMT) are disease recurrence, infection, the need for red blood cell and platelet transfusions, delayed or incomplete engraftment, organ damage from the ablative regimen, prolonged hospitalization, and high cost treatment. These same problems plus graft-versus host disease and graft rejection are also present in patients undergoing allogenic BMT in anticipation of reducing the severity of infectious complications, thereby decreasing hospitalization time, reducing costs and improving quality of life.
Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients: The mobilization of peripheral blood progenitor cells (PBPC) substitutes the autologous BMT. The major adverse reactions associated with the procedure are reduction in the platelet numbers and other haematopoietic elements. Use of Filgrastim to mobilize PBPC into the circulation for harvesting is expected to enhance progenitor numbers, lessen the frequency, duration and cost of leukapheresis procedures, potentially speed hematological recovery after transplantation of the CSF-mobilized cells and reduce the hospitalization.
Patients with Severe Chronic Neutropenia: Severe chronic neutropenia (SCN) (idiopathic, cyclic and congenital) is characterized by a selective decrease in the number of circulating neutrophils and an enhanced susceptibility to bacterial infections. The administration of Filgrastim has been shown to be safe and effective in causing a sustained increase in the neutrophil count and a decrease in infectious morbidity in treated patients.
Cancer Patients Receiving Myelosuppressive Chemotherapy: FILGRASTIM (LEUCOGEN) is indicated in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia and fever. A complete blood count (CBC) and platelet count should be obtained prior lo chemotherapy, and twice per week during FILGRASTIM (LEUCOGEN) therapy to avoid leukocytosis and to monitor the neutrophil count.
FILGRASTIM (LEUCOGEN) therapy should be discontinued when the ANC is >10,000/mm3 after the expected chemotherapy-induced nadir.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: FILGRASTIM (LEUCOGEN) is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML.
Cancer Patients Receiving Bone Marrow Transplant: FILGRASTIM (LEUCOGEN) is Indicated to reduce the duration of neutropenia and neutropenia-related clinical squeal, eg, febrile neutropenia, in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation. It is recommended that blood cells and platelet counts be obtained at a minimum of 3 times per week following marrow infusion to monitor the recovery of marrow reconstitution.
Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy: FILGRASTIM (LEUCOGEN) is indicated for the mobilization of haematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment after myeloablative chemotherapy.
Patients With Severe Chronic Neutropenia: FILGRASTIM (LEUCOGEN) is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia. It is essential that serial cell blood counts with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of FILGRASTIM (LEUCOGEN) therapy. The use of FILGRASTIM (LEUCOGEN) prior to confirmation of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition causing the neutropenia.
Pediatric Use In Severe Chronic Neutropenia and Cancer: FILGRASTIM (LEUCOGEN) is indicated for the treatment of the conditions previously described in pediatric patients. The efficacy and safety of FILGRASTIM (LEUCOGEN) are similar for adults and infants.
Cancer Patients Receiving Myelosuppressive Chemotherapy: The recommended starting dose of FILGRASTIM (LEUCOGEN) is 5 mcg/kg/day, administered as a single daily injection by SC bolus injection. A complete blood count and platelet count should be obtained before instituting FILGRASTIM (LEUCOGEN) therapy, and monitored twice weekly during therapy. Doses may be increased in increments or 5 mcg/kg for each chemotherapy cycle, according to the duration and severity of the absolute neutrophil count nadir. FILGRASTIM (LEUCOGEN) should be administered daily for up to 2 weeks, until the absolute neutrophil count has reached 10,000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of FILGRASTIM (LEUCOGEN) therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. FILGRASTIM (LEUCOGEN) therapy should be discontinued if the ANC surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir.
Cancer Patients Receiving Bone Marrow Transplant: The recommended dose of FILGRASTIM (LEUCOGEN) following bone marrow transplant is 10 mcg/kg/day given as an IV infusion or 4 or 24 hours. The first dose of FILGRASTIM (LEUCOGEN) should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery, the daily dose of FILGRASTIM (LEUCOGEN) should be titrated against the neutrophil response as follows: When ANC >1000/mm3 for 3 consecutive days the FILGRASTIM (LEUCOGEN) dose should be reduced to 5 mcg/kg/day. If ANC remains >1000/mm3 for 3 more consecutive days after the dose reduction, the treatment with FILGRASTIM (LEUCOGEN should be discontinued. If ANC decreases to <1000/mm3 the treatment should be resumed at 5 mcg/kg/day. If ANC decreases to <1000/mm3 at any time during the 5 mcg/kg/day administration, FILGRASTIM (LEUCOGEN) should be increased to 10 mcg/kg/day, and the above steps should then be followed. The treatment should be administered for 14 days.
Peripheral Blood Progenitor Cell Collection and Therapy In Cancer Patients: The recommended dose of FILGRASTIM (LEUCOGEN) for the mobilization of PBPC is 10 mcg/kg/day SC. It is recommended that FILGRASTIM (LEUCOGEN) be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis.
Neutrophil counts should be monitored after 4 days of FILGRASTIM (LEUCOGEN) and FILGRASTIM (LEUCOGEN) dose modification should be considered for those patients who develop a WBC count >100,000/mm3. FILGRASTIM (LEUCOGEN) for 6 to 7 days with leukapheresis on days 5, 6 and 7 is safe and effective.
Patients With Severe Chronic Neutropenia: Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patients' clinical course as well as ANC. The median daily doses are: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses >100 mcg/kg/day.
Patients With Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: FILGRASTIM (LEUCOGEN) should be administered at 5 mcg/kg/day given as subcutaneous bolus. The first dose or FILGRASTIM (LEUCOGEN) should be administered at least 24 hours after cytotoxic chemotherapy. FILGRASTIM (LEUCOGEN) therapy should be discontinued if the ANC surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir or for a maximal period of 35 days.
The maximum tolerated dose of FILGRASTIM (LEUCOGEN) has not been determined. It is not known the overdosage effect of FILGRASTIM (LEUCOGEN).
FILGRASTIM (LEUCOGEN) is contraindicated in patients with known hypersensitivity to E. coli-derived proteins. Filgrastim or any component of the product.
It is not known the safety effects of Filgrastim during pregnancy. In animals studies with Filgrastim, embryolethality were observed but not external abnormalities. FILGRASTIM (LEUCOGEN) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether FILGRASTIM (LEUCOGEN) is excreted in human milk. Because many drugs are excreted in human milk, the administration of FILGRASTIM (LEUCOGEN) is not recommended in a nursing woman.
Do not dilute with saline solutions at any time; product may precipitate. Do not shake the vial content. Vigorous shaking may denaturalize the glycoprotein and affect its biological activity.
General Simultaneous Use With Chemotherapy and Radiation Therapy: The safely and efficacy of FILGRASTIM (LEUCOGEN) given simultaneously with cytotoxic chemotherapy or concurrent radiation therapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, do not use FILGRASTIM (LEUCOGEN) in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. Simultaneous use of FILGRASTIM (LEUCOGEN) with chemotherapy and radiation therapy should be avoided.
Potential Effect on Malignant Cells: FILGRASTIM (LEUCOGEN) is a growth factor that primarily stimulates neutrophils. However, the possibility that FILGRASTIM (LEUCOGEN) can act as a growth factor for any tumor type cannot be excluded. The safety of FILGRASTIM (LEUCOGEN) in chronic myeloid leukemia (CML) and myelodysplasia has not been established.
Leukocytosis: White blood cell counts of 100,000/mm3 or greater were observed in approximately 2% of cancer patients receiving myelosuppressive chemotherapy, treated with Filgrastim at doses above 3 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis.
Premature Discontinuation of Therapy: The interruption of the Filgrastim treatment produce a 50% decrease of the circulating neutrophils in a period of 1 to 2 days with a normalization in a period of 1 to 7 days. A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of FILGRASTIM (LEUCOGEN) therapy. However, for a sustained therapeutic response, FILGRASTIM (LEUCOGEN) therapy should be continued following chemotherapy until the post nadir ANC reaches 10,000/mm3.
Other Specials cautions should be taken during the administration of higher doses of chemotherapy because the patient may be at greater risk of cardiac, pulmonary, neurological and dermatological toxicities. FILGRASTIM (LEUCOGEN) do not avoid thrombocytopenia or anemia as consequence of myelosuppressive chemotherapy therefore regular monitoring of the hematocrit and platelet count is recommended, especially when chemotherapeutic agents or combinations of them with severe thrombocytopenic effect are administered. Bone density should be determined in patients with osteoporosis receiving FILGRASTIM (LEUCOGEN) for period longer than 6 months. FILGRASTIM (LEUCOGEN) is not recommended ln patients with severe hepatic or renal dysfunction. In septic patients receiving FILGRASTIM (LEUCOGEN), the physician should be alert to the possibility of adult respiratory distress syndrome, due to the possible influx of neutrophils at the site of inflammation.
The administration of the recommended doses of Filgrastim is commonly associated with medullary bone pain generally reported to be of mild to moderate severity and could be controlled in most patients with non-narcotic analgesics at conventional doses. Mild to moderate dysuria and transient decreases in blood pressure are the secondary effects less frequently reported ad do not require treatment. Spontaneously reversible and dose dependent elevations in uric acid, lactate dehydrogenase and alkaline phosphatase occurred during FILGRASTIM (LEUCOGEN) therapy. White blood cell counts of 100,000/mm3
or greater were observed in cancer patients receiving Filgrastim at doses above 3 mcg/kg/day. There were no reports of adverse effects associated to chemotherapy: Nausea, vomiting, alopecia, diarrhea, anorexia, fever, fatigue, mucositis, headache, constipation, skin rash, cough and thoracic pain are not increased in patients receiving Filgrastim treatment. There have been rare reports of cutaneous vasculitis in patients treated with Filgrastim. Symptoms of vasculitis generally developed simultaneously with an increase in the absolute neutrophils counts.
It is not known the safety and efficacy of FILGRASTIM (LEUCOGEN) given simultaneously with cytotoxic myelosuppressive chemotherapy. Do not use FILGRASTIM (LEUCOGEN) in the period of 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. Drug interactions between FILGRASTIM (LEUCOGEN) and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils, such as lithium should be used with caution.
Preparation: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip off from the vial containing FILGRASTIM (LEUCOGEN), and wipe the rubber stopper with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution If required, FILGRASTIM (LEUCOGEN) may be diluted in 5% dextrose. FILGRASTIM (LEUCOGEN) diluted to concentrations between 5 and 15 mcg/ml should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/ml. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human), FILGRASTIM (LEUCOGEN) is compatible with glass and plastic bottles and materials. Dilution of FILGRASTIM (LEUCOGEN) to a final concentration of less than 5 mcg/ml is not recommended at any time.
FILGRASTIM (LEUCOGEN) should be stored in the refrigerator at 2° to 8°C. Avoid freezing or shaking.
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Soln for inj (vial) 300 mcg/mL (sterile, clear, colorless, preservative-free in a buffered solution) x 1 mL x 10's.