Filgrastim was approved in the US in 1991 and is the originator short-acting recombinant methionyl human G-CSF. It has since remained in use with long-acting versions (pegfilgrastim) and biosimilars increasingly being made since the originator approval with similar indications. This article focuses on the originator filgrastim.
Filgrastim is a recombinant human methionyl granulocyte colony-stimulating factor(G-CSF) which stimulates the proliferation, maturation of neutrophil progenitors, and functional end-cell activation. It also facilitates their release into the blood.
Filgrastim exhibits nonlinear pharmacokinetics with a short half-life of 3.5 hours, with filgrastim concentration and neutrophil count being the determinants of clearance. The kidneys clear the drug.
The bioavailability of filgrastim after subcutaneous administration is 60 to 70%.
Filgrastim is available as a clear colorless preservative clear liquid in single-dose vials(300 mcg/ml or 480 mcg/1.6ml) or single-dose prefilled syringes(300 mcg/0.5ml or 480 mcg/0.8ml) which is administered subcutaneously or intravenously.
It should NOT be administered 24 hours before and after receiving cytotoxic chemotherapy. Safety and efficacy of the simultaneous use of filgrastim and cytotoxic chemotherapy have not undergone evaluation.
In cancer patients receiving myelosuppression therapy/adults with AML-
Recommended starting dose is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes) ‚ or by continuous SC or IV infusion.
Doses can be titrated by 5 mcg/kg/day for each chemotherapy cycle, depending on the duration and severity of cytotoxicity.
The recommendation is to administer filgrastim for up to 2 weeks or until ANC is 10000/mm^3. Discontinue drug if ANC>10000/mm^3.
Patients with non-myeloid malignancies undergoing myeloablative therapy following Bone Marrow Transplantation (BMT): Starting dose is 10 mcg/kg via short IV infusion (over 15 to 30 minutes) or continuous IV infusion administered at least 24hrs after BMT or cytotoxic chemotherapy. Dosage adjustment for neutrophil recovery Following BMT via short IV infusion (over 15 to 30 minutes) or continuous IV infusion:
If ANC <1000/mm3 while receiving 5 mcg/kg/day: Increase to 10 mcg/kg and repeat the above dose adjustment steps.
Patients undergoing Peripheral Blood Progenitor Collection(PBPC) and therapy
The recommended dose of filgrastim for the mobilization of PBPC is 10 mcg/kg/day subcutaneously‚ either as a bolus or a continuous infusion.
The recommendation is to give filgrastim for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis.
Patients with Severe Chronic Neutropenia
Confirm diagnosis before starting treatment.
In the severe chronic neutropenia post-marketing surveillance study, the median daily dose was:
Doses administered via subcutaneous injection
Patients with Radiation-Induced Neutropenia
Pediatric and Pregnant Female population-
Pharmacokinetics in pediatric patients after chemotherapy is the same as adults with weight-based adjusted doses. There are safety and efficacy studies that have been conducted on the severe chronic neutropenia and PBPC population, revealing no significant adverse effects.
The drug is pregnancy category C. There are very few studies evaluating the efficacy and safety of the drug in pregnant women. Observational studies reported no association between filgrastim use and pregnancy outcomes, neonatal complications, or infections. The clinician should weigh the benefits and risks before administering the drug to these patients.
Bone pain is the most commonly reported adverse effect of filgrastim.
A systematic literature review by Dale et al. reported bone pain and other musculoskeletal symptoms as being the most common adverse effect of filgrastim while also noting the incidence of other adverse effects that were not as significant in comparison.
The various adverse reactions noted in clinical trials that can occur in the different subsets of patients for which filgrastim is indicated for include:
Other adverse effects reported since filgrastim's approval are as follows-
There is limited data on the incidence or frequency of these adverse effects. There have been a few reports of incidence of acute myelogenous leukemia (AML) and/or myelodysplastic syndrome in certain populations receiving filgrastim, especially patients with congenital neutropenia. The Severe Chronic Neutropenia International Registry published a 10-year report in 2003 on the incidence of AML/myelodysplastic syndrome occurring in 35 of 387 patients with congenital neutropenia, but no established no relationship to dose and duration of filgrastim.
Filgrastim is contraindicated in patients with allergic reactions to E. coli-derived proteins, filgrastim, or any component of the product.
The recommended starting dosage is usually 5mcg/kg or 10mcg/kg, depending on the indication, as noted earlier. There has been very limited data regarding the maximum tolerable dosage of filgrastim. Although rare, doses of up to and even greater than 100 mcg/kg have been used in individuals with minimal toxic effects.
Some studies noted a plateau in dose-response curves when the dosage exceeded 10 mcg/kg in bone marrow transplant patients.
Baseline CBC and platelet counts should be obtained prior to administration and following filgrastim administration.
The following are the required monitoring parameters:
It is advised not to use filgrastim with concurrent chemotherapy and radiotherapy due to a lack of safety and efficacy studies.
There is minimal data regarding the maximum tolerable dosage. Adverse effects that occur with filgrastim use mainly resolve following discontinuation of the drug. Some are manageable with supportive measures e.g., bone pain, which is a common side effect usually managed with analgesics. Monitoring is essential to track response and minimize complications.
Although rare(<5%), Leukocytosis with WBC >100,000/mm^3 has been observed in BMT patients with minimal adverse effects. The recommendation is to discontinue the drug if it occurs to prevent potential complications.
There is no antidote for reversal of filgrastim.
Filgrastim requires an interprofessional healthcare team approach, including clinicians, nurses, and pharmacists. Although it has uses in other fields of medicine, its primary use is in the field of hematology and oncology for reducing the duration of neutropenia in cancer patients undergoing chemotherapy or patients with myelosuppression. Clinicians should prioritize monitoring patients as monitoring is essential to track the response and minimize complications. Nurses should be aware of the proper way of drug administration and be alert to signs of infection and adverse effects. Pharmacists are also crucial for appropriate dosing schedules. The principal aim of filgrastim is to reduce the incidence of infection manifested by febrile neutropenia in patients receiving myelosuppressive chemotherapy. Thus, being alert to signs of infection would guide dosage and improve response outcomes in these patients. [Level 5]
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