Actions of Filastin in details
Pharmacotherapeutic Group: Haematopoietic growth factor (cytokines).
Pharmacology: Pharmacodynamics: Mechanism of Action: Human granulocyte colony-stimulating factor (G-CSF) is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Filastin, containing r-metHuG-CSF (Filastin), causes marked increases in peripheral blood neutrophil counts within 24 hrs, with minor increases in monocytes. In some severe chronic neutropenia patients, Filastin can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment.
Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced by the human body in response to Filastin show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of Filastin therapy, circulating neutrophil counts decrease by 50% within 1-2 days and to normal levels within 1-7 days.
Treatment with Filastin in patients undergoing cytotoxic chemotherapy or myeloablative therapy followed by bone marrow transplantation leads to a significant reduction in the incidence, severity and duration of neutropenia and febrile neutropenia and consequently, fewer admissions to the hospital, shorter duration of hospitalization and less antibiotics as compared to patients on cytotoxic chemotherapy alone.
Treatment with Filastin significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalization after induction chemotherapy for acute myelogenous leukaemia. The incidence of fever and documented infections was not reduced in this setting.
Use of Filastin, either alone or after chemotherapy, mobilizes haematopoietic progenitor cells into the peripheral blood. These autologous peripheral blood progenitor cells (PBPCs) may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.
Recipients of allogeneic peripheral blood progenitor cells mobilized with Filastin experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.
Use of Filastin in patients, children or adults, with severe chronic neutropenia (severe congenital, cyclic and idiopathic neutropenia) induces a sustained increase in absolute neutrophil counts (ANC) in peripheral blood and a reduction of infection and related events.
Use of Filastin in patients with human immunodeficiency virus (HIV) infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with HIV infection treated with Filastin show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
Pharmacokinetics: Absorption: After SC administration, Filastin is rapidly absorbed, and peak serum concentrations are attained 2-8 hrs after dosing. Elimination half-life (t½) after IV and SC dosing is usually between 2 hrs and 4 hrs. Clearance and t½ are dependent on dose and neutrophil count. When neutrophil-mediated clearance is saturated by high Filastin concentrations or is diminished by neutropenia, the linear clearance pathway predominates and the pharmacokinetics appear linear. The absolute bioavailability of Filastin after SC administration is estimated to be 62% for a 375-mcg dose and 72% for a 750-mcg dose. After discontinuation of dosing, Filastin concentrations decrease to endogenous concentrations within 24 hrs.
A decrease in Filastin serum concentrations is evidenced upon multiple dosing in healthy subjects and in cancer subjects before chemotherapy. This increase in clearance of Filastin is dose-dependent, and the magnitude of increase appears closely related to the degree of neutrophilia in the recipients, which is consistent with increased neutrophil-mediated clearance by the expanded neutrophil pool. In subjects receiving Filastin after chemotherapy, plateau serum concentrations are maintained until onset of haematopoietic recovery.
Distribution: There is a positive linear correlation between the dose and the serum concentration of Filastin, whether administered IV or SC. Following SC administration of recommended doses, serum concentrations were maintained >10 ng/mL for 8-16 hrs. The volume of distribution in blood is approximately 150 mL/kg.
Elimination: Continuous infusion with Filastin over 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 t½.
Clearance of Filastin has been shown to follow 1st-order pharmacokinetics after both SC and IV administration. The mean serum elimination t½ of Filastin is approximately 3.5 hrs, with a clearance rate of approximately 0.6 mL/min/kg.
Special Populations: Paediatrics: The pharmacokinetics of Filastin in paediatric patients after chemotherapy is similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of Filastin.
Geriatrics: Pharmacokinetic data in geriatric patients (>65 years) are not available.
Renal or Hepatic Impairment: Studies of Filastin 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. A trend towards higher systemic exposure to Filastin is observed in patients with end-stage renal disease (ESRD) compared with healthy subjects and subjects with creatinine clearance of 30-60 mL/min.
Toxicology: Preclinical Safety Data: Carcinogenicity: The carcinogenic potential of Filastin has not been studied. Filastin failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system.
Certain malignant cells have been shown to express G-CSF receptors. The possibility that Filastin can act as growth factor for any tumor type cannot be excluded.
Impairment of Fertility: Filastin had no observed effect on the fertility of male or female rats, or gestation, at doses up to 500 mcg/kg.
Teratogenicity: There is no evidence from studies in rats and rabbits that Filastin is teratogenic. An increased incidence of embryo loss has been observed in rabbits, but no malformation has been seen.
How should I take Filastin?
A nurse or other trained health professional may give you Filastin. Filastin is given as a shot under your skin or into a vein.
You may be taught how to give Filastin at home. Make sure you understand all of the instructions before giving yourself an injection. Use Filastin only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.
Filastin comes with patient instructions. Read and follow these instructions carefully. Ask your doctor if you have any questions about:
- How to prepare the injection.
- The proper use of disposable syringes.
- How to give the injection.
- How long the injection can be stored at home.
If you use the prefilled syringe, make sure you know how to use the needle guard. After giving an injection, slide the needle guard forward over the needle until you hear a "click." The needle guard will safely cover the used needle.
Each syringe or vial of medicine is good for only one dose. Throw the syringe or vial away after your dose. Do not save unused medicine from an opened vial or syringe.
Dosing
The dose of Filastin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Filastin. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For injectable dosage form:
- For neutropenia:
- Adults and children—Dose is based on body weight and must be determined by your doctor.
- Infants younger than 1 month of age—Use and dose must be determined by your doctor.
- For neutropenia:
Missed Dose
Filastin needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.
Storage
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Store in the refrigerator. Do not freeze.
Leave the medicine in the carton until you are ready to use it. If you accidentally freeze the medicine, let it thaw out in the refrigerator before you use it. If you accidentally freeze the medicine a second time, do not use it.
You may let the medicine warm up to room temperature before you use it. The medicine can stay out of the refrigerator for up to 24 hours. Discard any medicine that has been out of the refrigerator for more than 24 hours.
Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.
Filastin administration
Filastin should not be given within the 24-hour period before or after you receive chemotherapy.
Filastin is injected into a vein or under the skin. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, syringes, IV tubing, and other items used to inject the medicine.
Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
Do not shake the medication bottle or prefilled syringe, or you may ruin the medicine. Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.
Use a different place on your arms, stomach, hips, or legs each time you give the injection. Your care provider will show you the best places on your body to inject the medication. Do not inject into the same place two times in a row.
A Filastin vial or prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left inside. Do not use Filastin if the expiration date on the label has passed. Call your doctor for a new prescription.
Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.
To be sure this medication is helping your condition, your blood may need to be tested often. This will help your doctor determine how long to treat you with Filastin. Your liver function will also need to be tested, and you may need bone density scans. Visit your doctor regularly.
Store this medication in the refrigerator and do not allow it to freeze. You may allow the medication to reach room temperature for 24 hours before measuring your dose in a syringe. Then place the vial back in the refrigerator. Throw away any Filastin that has been left out at room temperature for longer than 24 hours.
Filastin pharmacology
12.1 Mechanism of Action
Colony-stimulating factors are glycoproteins which act on hematopoietic 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 that is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody-dependent killing, and the increased expression of some 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 or activity of hematopoietic cell types other than the neutrophil lineage.
12.2 Pharmacodynamics
In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ Filastin administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. This increase in neutrophil counts was observed whether Filastin was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/kg/day). With discontinuation of Filastin therapy‚ neutrophil counts returned to baseline in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro.
The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving Filastin; however‚ the percentage of monocytes in the differential count remained within the normal range. Absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of Filastin. Increases in lymphocyte counts following Filastin administration have been reported in some normal subjects and patients with cancer.
White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection.
12.3 Pharmacokinetics
Filastin exhibits nonlinear pharmacokinetics. Clearance is dependent on Filastin concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of Filastin and is diminished by neutropenia. In addition, Filastin is cleared by the kidney.
Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of Filastin resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and cancer subjects. Clearance rates of Filastin were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following Filastin dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 to 20-day period produced steady-state serum concentrations of Filastin with no evidence of drug accumulation over the time period investigated. The absolute bioavailability of Filastin after subcutaneous administration is 60% to 70%.
Specific Populations
Patients Acutely Exposed to Myelosuppressive Doses of Radiation
The pharmacokinetics of Filastin is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to Filastin in non-human primates at 10 mcg/kg dose of Filastin, appears to be similar to that in humans at 5 mcg/kg. Simulations conducted using the population pharmacokinetic model indicates that the exposures to Filastin at a Filastin dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.
Pediatric Patients
The pharmacokinetics of Filastin in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of Filastin.
Renal Impairment
In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (n=4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.
Hepatic Impairment
Pharmacokinetics and pharmacodynamics of Filastin are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, Filastin dose adjustment for patients with hepatic impairment is not necessary.
Reviews
The results of a survey conducted on ndrugs.com for Filastin are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Filastin. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
