Filgrastim is a human granulocyte colony stimulating factor (r-met-Hu-G-CSF), which is produced by recombinant DNA technology. Filgrastim is a 175 amino acid nonglycosylated protein, with a molecular weight of 18,000 D. Leuco-Plus is produced by Escherichia coli (E. Coli) bacteria into which has been inserted the human granulocyte colony stimulating factor gene.
Each ml of solution contains 30 million units (MU) (equivalent to 300 micrograms [μg]) Filgrastim.
Each vial/prefilled syringe contains 30 MU (equivalent to 300 μg) Filgrastim in 1 ml.
Excipients/Inactive Ingredients: Sorbitol, Polysorbate 80, Sodium Acetate, Acetic acid and Water for injection.
Pharmacology: Human G-CSF is a glycoprotein that regulates production and release of functional neutrophils from bone marrow. Leuco-Plus 300 (Vial/Prefilled Syringe) contains r-met-Hu-G-CSF (Filgrastim) that increases considerably neutrophil count in peripheral blood at 24 hours and minimally monocyte count. It also induces a mild increase of circulating eosinophils and basophils with respect to the initial values in some patients with severe chronic neutropenia; some of these patients show eosinophils or basophils even before treatment. Neutrophils increase depends on the dose, when the recommended dosage is applied. Neutrophils produced in response to treatment show a normal or superior than usual function, according to chemotactic and phagocytic function tests. After interrupting treatment count of circulating neutrophils is reduced in 50% in 1-2 days and it normalizes in a period of 1 to 7 days.
The rapid systemic depuration rhythms and relatively short half-life observed with G-CSF in prior studies with different species is a typical pharmacokinetic behavior of biological molecules. Product clearance follows a first order pharmacokinetics after its subcutaneous and intravenous administration. The elimination half-life is approximately 3.5 hours with a clearance of approximately 0.6 ml/min/kg. The continuous infusion along periods of up to 28 days in patients that recover from autologous bone marrow transplantation is not associated to pharmacological accumulation and elimination half-life are comparable. There is a positive linear correlation between the dose and the serum concentration when administered both by intravenous and subcutaneous route. Serum concentrations remain above 10 ng/ml during 8 to 16 hours after the subcutaneous administration of the recommended dose. The distribution volume in blood is approximately 150 ml/kg.
Pharmacological Actions: 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 count 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 Neutrophils Count (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 the high cost of treatment. These same problems plus graft-versus-host disease and graft rejection are also present in patients undergoing allogeneic BMT. Filgrastim have been administered following both autologous and allogeneic BMT in anticipation of reducing the severity of infectious complications, thereby decreasing hospitalization time, reducing costs, and improving quality of life.
Peripheral Blood Progenitor Cells 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 platelets numbers and other hematopoietic 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 leukopheresis 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.
Patients with HIV/AIDS: The use of Filgrastim in HIV-infected patients remains the normal number of neutrophils to allow controlled dosage of antivirals and other myelosuppressive medications. There are not evidences that HIV replication increase in HIV-positive patients treated with Filgrastim.
Cancer Patients Receiving Myelosuppressive Chemotherapy: Filgrastim is indicated in patients with non-myeloid 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 to chemotherapy, and twice per week during Filgrastim therapy to avoid leukocytosis and to monitor the neutrophil count. Filgrastim therapy should be discontinued when the ANC ≥10,000/mm3 after the expected chemotherapy-induced nadir.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: Filgrastim 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 is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with non-myeloid malignancies undergoing myelo-ablative 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 is indicated for the mobilization of hematopoietic 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 is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g. 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 therapy. The use of Filgrastim 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 is indicated for the treatment of the conditions previously described in pediatric patients. The efficacy and safety of Filgrastim are similar for adults and infants.
Prophylaxis and Treatment of Neutropenia in Patients with HIV/AIDS: Filgrastim is indicated in patients with neutropenic episodes associated with viral replication (HIV) or opportunistic infections in HIV/AIDS patients receiving anti-retroviral treatment like prophylaxis and patients with neutropenia secondary to chemotherapy and/or radiotherapy for malignant disease associated with their base disease.
Recommended Dose: Cancer Patients Receiving Myelosuppressive Chemotherapy: The recommended starting dose of Filgrastim is 5 μg/kg/day, administered as a single daily injection by SC bolus injection or by rapid intravenous infusion (15-30 minutes). A complete blood count and platelet count should be obtained before instituting Filgrastim therapy, and monitored twice weekly during therapy. Doses may be increased in increments of 5 μg/kg for each chemotherapy cycle, according to the duration and severity of the absolute neutrophil count nadir.
Filgrastim 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 therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. Filgrastim 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 following bone marrow transplant is 10 μg/kg/day given as an intravenous infusion of 4 to 24 hours. The first dose of Filgrastim 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 should be titrated against the neutrophil response as follows: When ANC >1,000/mm3 for 3 consecutive days the Filgrastim dose should be reduced to 5 μg/kg/day.
If ANC remains >1,000/mm3 for 3 more consecutive days after the dose reduction should stop treatment, once ANC decreases to <1,000/mm3 the treatment should be resumed at 5 μg/kg/day.
If ANC decreases to <1,000/mm3 at any time during the 5 μg/kg/day administration, Filgrastim should be increased to 10 μg/kg/day.
The treatment should be administered for 14 days consecutives.
Cancer Patients Undergoing Mobilization Procedure and Collection of Hematopoietic Progenitor Cells: The recommended dose of Filgrastim for the mobilization of PBPC is 10 μg/kg/day by subcutaneous or intravenous. It is recommended that Filgrastim 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, and Filgrastim dose modification should be considered for those patients who develop a WBC count >100,000/mm3. Filgrastim for 6 to 7 days with leukaphereses on days 5, 6, and 7 is safe and effective.
Patients with Severe Chronic Neutropenia: 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 dose ranging from 1.2 μg/kg (idiopathic neutropenia); 2.1 μg/kg (neutropenia cyclic), 6.0 μg/kg (congenital neutropenia) to exceptional cases of congenital neutropenia that required doses greater than 100 μg/kg/day.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: Filgrastim should be administered at 5 μg/kg/day by subcutaneous. The first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy. The treatment with Filgrastim should be discontinued if the ANC surpasses 100,000/mm3 after the expected chemotherapy-induced neutrophil nadir or for a maximal period of 35 days.
Prophylaxis and Treatment of Neutropenia in Patients with HIV/AIDS: To correct the neutropenia the recommended starting dose of Filgrastim is 5 μg/kg/day to achieve and maintain a normal number of neutrophils (ANC >2.0 x 109/L).
To maintain the neutrophil count within normal limits: Once corrected neutropenia, should determine the minimum effective dose needed to maintain a normal number of neutrophils.
It is recommended to adjust the initial dose to 30 MU (300 μg)/day SC injection on alternate days. Sometimes it may be necessary to further adjust the dose according to the ANC of the patient to keep the number of neutrophils above 2.0 x 109/L.
In the prophylaxis of neutropenia associated with chemotherapy and/or radiotherapy described dosages are recommended for patients with cancer receiving myelosuppressive chemotherapy.
Allowed increases in initial dose of 5 μg/kg to 10 μg/kg in subsequent neutropenic episodes according to the duration and severity of neutropenia above.
Mode of Administration: Administered as a single daily injection by subcutaneous injection or by intravenous infusion.
The maximum tolerated dose of Filgrastim has not been determined. It is not known the overdosing effect of Filgrastim.
Leuco-Plus 300 (Vial/Prefilled Syringe) is contraindicated in patients with known hypersensitivity to E. coli-derived proteins, Filgrastim, or any component of the product. Severe congenital neutropenia with abnormal cytogenetics.
Simultaneous Use with Chemotherapy and Radiation Therapy: The safety and efficacy of Filgrastim 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 in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. Simultaneous use of Filgrastim with chemotherapy and radiation therapy should be avoided.
Potential Effect on Malignant Cells: Filgrastim is a growth factor that primarily stimulates neutrophils. However, the possibility that Filgrastim can act as a growth factor for any tumor type cannot be excluded. The safety of Filgrastim 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 μg/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 therapy. However, for a sustained therapeutic response, Filgrastim 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 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 for period longer than 6 months.
Filgrastim is not recommended in patients with severe hepatic or renal dysfunction.
In septic patients receiving Filgrastim, the physician should be alert to the possibility of adult respiratory distress syndrome, due to the possible influx of neutrophil at the site of inflammation.
Adverse effects of Filgrastim during pregnancy is unknown. Studies in animals show that Filgrastim increases the incidence of embryonary losses but not of malformations. The relation between the therapeutic benefit and the possible fetal risks should be assessed before using Filgrastim in pregnant women. It is unknown if Filgrastim is secreted in maternal milk thus its use is not recommended in breastfeeding women.
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 and do not required treatment. Spontaneously reversible and dose dependent elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase occurred during Filgrastim therapy. White blood cell counts of 100,000/mm3
or greater were observed in cancer patients receiving Filgrastim at doses above 3 μg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis.
The incidence 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 neutrophil count.
It is not known the safety and efficacy of Filgrastim given simultaneously with cytotoxic myelosuppressive chemotherapy. Do not use Filgrastim in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. Drug interactions between Filgrastim 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: 1. Leave Leuco-Plus 300 (Vial/Prefilled Syringe) from the refrigerator to allow the solution to reach room temperature before administration.
2. Inspected visually for particulate matter and discoloration prior to administration. Do not use if discoloration is present. Discard any unused solution.
3. Do not shake. Vigorous shaking may denature the glycoprotein and render it biologically inactive.
4. Leuco-Plus 300 (Vial/Prefilled Syringe) is used for subcutaneous injection or Intravenous Infusion administration.
5. If required, Leuco-Plus 300 (Vial/Prefilled Syringe) may be diluted in 5% dextrose. Leuco-Plus 300 diluted to concentrations between 5 and 15 μg/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), Leuco-Plus 300 compatible with glass and plastic bottles and materials.
6. Dilution of Leuco-Plus 300 (Vial/Prefilled Syringe) to a final concentration of less than 5 μg/ml is not recommended at any time.
7. Do not dilute with saline solutions at any time; product may precipitate.
8. Leuco-Plus 300 (Vial), using aseptic technics, attach a sterile needle to a sterile syringe. Remove the flip off from the vial containing Leuco-Plus, and wipe the rubber stopper with disinfactant. Insert the needle into the vial, and withdraw into the syringe with an appropriated volume of solution.
Leuco-Plus 300 (Vial/Prefilled Syringe) should be stored in the refrigerator at 2°C to 8°C. Avoid shaking.
Shelf-Life: 24 months.
L03AA02 - filgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.
Soln for inj (vial) (sterile, clear, colorless, preservative-free liquid in a buffered solution) 300 mcg/mL x 1's, (pre-filled syringe) 300 mcg/mL x 1's. 480 mcg/mL x 1's.