Colony Stimulating Factors

Note: In patients receiving epoetin alfa 2-3 times per week, darbepoetin alfa is administered once weekly. In patients who are receiving epoetin alfa once weekly, darbepoetin should be administered once every 2 weeks.

Dosage adjustment: Goal: Dose should be adjusted to achieve and maintain a target hemoglobin not to exceed 12 g/dL.
Inadequate response: Hemoglobin increases <1 g/dL over 4 weeks and iron stores are adequate: Increase by ~25% of the previous dose; increases should not be made more frequently than once monthly.
Excessive response: Hemoglobin increases >1 g/dL in any 2-week period: Decrease dose Hemoglobin increases and approaches the target value of 12 g/dL: Decrease weekly dosage by ~25%. If hemoglobin continues to increase, hold dose temporarily until hemoglobin begins to decrease, then restart at a dose 25% below the previous dose.

Correction of anemia associated with cancer patients receiving chemotherapy: Initial: 2.25 mcg/kg SQ once weekly. Adjust dose as follows to achieve and maintain a target hemoglobin:
Inadequate response: Hemoglobin increases <1 g/dL after 6 weeks of therapy: Increase dose to 4.5 mcg/kg.
Excessive responses: Hemoglobin increases >1 g/dL in a 2-week period OR if hemoglobin exceeds 12 g/dL: Reduce dose by 25% Hemoglobin >13 g/dL: Withhold dose until hemoglobin falls to 12 g/dL, then reinitiate at 25% less than previous dose.

Darbepoetin's T1/2 is approximately 3 times that of epoetin alfa.

AZT-treated, HIV infected patients: 100 units/kg IV/SC 3 times/week x 8 weeks. Increase dose by 50-100 units/kg 3 times/week if response is not satisfactory in terms of reducing transfusion requirements or increasing hemoglobin after 8 weeks of therapy. Evaluate response every 4-8 weeks thereafter and adjust the dose accordingly by 50-100 units/kg increments 3 times/week. If patient has not responded satisfactorily to a 300 unit/kg dose 3 times/week, a response to higher doses is unlikely. Stop dose if hemoglobin exceeds 13 g/dl and resume treatment at a 25% dose reduction when hemoglobin drops to 12 g/dl.

Cancer patients on chemotherapy (Treatment of patients with erythropoietin levels >200 mU/mL is not recommended). 150 units/kg SC 3 times/week or 40,000 units once weekly. Dose adjustment: If response is not satisfactory after a sufficient period of evaluation (8 weeks of 3 times/week and 4 weeks of once weekly therapy), the dose may be increased every 4 weeks (or longer) up to 300 units/kg 3 times/week, or when dosed weekly, increased all at once to 60,000 units weekly. If patient does not respond, a response to higher doses is unlikely.

Surgery patients: Prior to initiating treatment, obtain a hemoglobin to establish that is >10 mg/dL or 13 mg/dL: Initial dose: 300 units/kg/day SC x 10 days before surgery, on the day of surgery, and for 4 days after surgery. Alternative dose: 600 units/kg in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.

Endogenous G-CSF is a lineage specific colony-stimulating factor which 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 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 hematopoietic cell types other than the neutrophil lineage.

Dosing:
Dosing, even in morbidly obese patients, should be based on actual body weight. Rounding doses to the nearest vial size often enhances patient convenience and reduces costs without compromising clinical response.

Myelosuppressive therapy: 5 mcg/kg/day - doses may be increased by 5 mcg/kg according to the duration and severity of the neutropenia.

Bone marrow transplantation: 5-10 mcg/kg/day - doses may be increased by 5 mcg/kg according to the duration and severity of neutropenia; recommended steps based on neutrophil response:

When ANC >1000/mm3 for 3 consecutive days: Reduce filgrastim dose to 5 mcg/kg/day
If ANC remains >1000/mm3 for 3 more consecutive days: Discontinue filgrastim
If ANC decreases to <1000/mm3 : Resume at 5 mcg/kg/day
If ANC decreases <1000/mm3 during the 5 mcg/kg/day dose, increase filgrastim to 10 mcg/kg/day and follow the above steps

Peripheral blood progenitor cell (PBPC) collection: 10 mcg/kg/day or 5-8 mcg/kg twice daily in donors. The optimal timing and duration of growth factor stimulation has not been determined.

Severe chronic neutropenia:
Congenital: 6 mcg/kg twice daily
Idiopathic/cyclic: 5 mcg/kg/day

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9222

Supplied:
Injection, solution [preservative free]: 300 mcg/mL (1 mL, 1.6 mL) [vial; contains sodium 0.035 mg/mL and sorbitol]

Injection, solution [preservative free]: 600 mcg/mL (0.5 mL, 0.8 mL) [prefilled Singleject® syringe; contains sodium 0.035 mg/mL and sorbitol]

Comparative Effects G-CSF vs GM-CSF

Drug UPDATES:   ZARXIO ™- filgrastim-sndz injection
[Drug information  /  PDF]    Click link for the latest monograph
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2015

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.

INDICATIONS AND USAGE:
1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy
ZARXIO is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever [see Clinical Studies (14.1)].

1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy
ZARXIO is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) [see Clinical Studies (14.2)].

1.3 Patients with Cancer Undergoing Bone Marrow Transplantation
ZARXIO is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies (14.3)].

1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy
ZARXIO is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4)].

1.5 Patients with Severe Chronic Neutropenia
ZARXIO 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

HOW SUPPLIED:
Injection: 300 mcg/0.5 mL in a single-use prefilled syringe with BD UltraSafe Passive ™ Needle Guard
Injection: 480 mcg/0.8 mL in a single-use prefilled syringe with BD UltraSafe Passive ™ Needle Guard

CLINICAL PHARMACOLOGY
The primary hematopoietic activity of Neumega is stimulation of megakaryocytopoiesis and thrombopoiesis. Neumega has shown potent thrombopoietic activity in animal models of compromised hematopoiesis, including moderately to severely myelosuppressed mice and nonhuman primates. In these models, Neumega improved platelet nadirs and accelerated platelet recoveries compared to controls.

Preclinical trials have shown that mature megakaryocytes which develop during in vivo treatment with Neumega are ultrastructurally normal. Platelets produced in response to Neumega were morphologically and functionally normal and possessed a normal life span.

IL-11 has also been shown to have non-hematopoietic activities in animals including the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis, inhibition of pro-inflammatory cytokine production by macrophages, and the stimulation of osteoclastogenesis and neurogenesis. Non-hematopoietic pathologic changes observed in animals include fibrosis of tendons and joint capsules, periosteal thickening, papilledema, and embryotoxicity

INDICATIONS AND USAGE
Neumega is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. Neumega is not indicated following myeloablative chemotherapy (see package insert for WARNINGS, Increased Toxicity Following Myeloablative Therapy). The safety and effectiveness of Neumega have not been established in pediatric patients.

CONTRAINDICATIONS
Neumega is contraindicated in patients with a history of hypersensitivity to Neumega or any component of the product

Dosage
SubQ: Note: First dose should not be administered until 24-36 hours after the end of chemotherapy. Discontinue the drug at least 48 hours before beginning the next cycle of chemotherapy.
Children: 75-100 mcg/kg once daily for 10-21 days (until postnadir platelet count >/= 50,000 cells/ uL)

Note: The manufacturer states that, until efficacy/toxicity parameters are established, the use of oprelvekin in pediatric patients (particularly those <12 years of age) should be restricted to use in controlled clinical trials.

Adults: 50 mcg/kg once daily for 10-21 days (until postnadir platelet count >/= 50,000 cells/uL)

Administration
Subcutaneously in either the abdomen, thigh, or hip (or upper arm if not self-injected). Discontinue treatment with oprelvekin >/= 2 days before starting the next planned cycle of chemotherapy.

Supplied
Injection, powder for reconstitution: 5 mg

INDICATIONS AND USAGE
Neulasta® is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia

CONTRAINDICATIONS
Neulasta® is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product.

WARNINGS

General
The safety and efficacy of Neulasta® for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta® should not be used for PBPC mobilization.

Splenic Rupture
RARE CASES OF SPLENIC RUPTURE HAVE BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA®. SPLENIC RUPTURE, IN SOME CASES RESULTING IN DEATH, HAS ALSO BEEN ASSOCIATED WITH FILGRASTIM, THE PARENT COMPOUND OF NEULASTA®. PATIENTS RECEIVING NEULASTA® WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.

Adult Respiratory Distress Syndrome (ARDS)
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis receiving Filgrastim, the parent compound of Neulasta®, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Neulasta® who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta® should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition.

Allergic Reactions
Allergic reactions to Neulasta®, including anaphylaxis, skin rash, and urticaria, have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta® should be permanently discontinued in patients with serious allergic reactions.

Sickle Cell Disease
Severe sickle cell crises have been associated with the use of Neulasta® in patients with sickle cell disease. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disease should prescribe Neulasta® for such patients, and only after careful consideration of the potential risks and benefits.

Dosage
SubQ: Adolescents >45 kg and Adults: 6 mg once per chemotherapy cycle; do not administer in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy; do not use in patients, infants, children, and smaller adolescents weighing <45 kg

Monitoring Parameters
Complete blood count and platelet count should be obtained prior to chemotherapy. Leukocytosis (white blood cell counts 100,000/mm3 ) has been observed in <1% of patients receiving pegfilgrastim. Monitor platelets and hematocrit regularly.

Supplied
Injection, solution [preservative free]: 10 mg/mL (0.6 mL) [prefilled syringe]

Limitations of Use
OMONTYS is not indicated and is not recommended for use:

In patients with CKD not on dialysis .
In patients receiving treatment for cancer and whose anemia is not due to CKD.
As a substitute for RBC transfusions in patients who require immediate correction of anemia.
OMONTYS has not been shown to improve symptoms, physical functioning or health-related quality of life.

DOSAGE AND ADMINISTRATION
Initial treatment: 0.04 mg/kg body weight administered once monthly.
Conversion from another ESA: dose once monthly based on the total weekly epoetin or darbepoetin alfa dose at the time of conversion.

DOSAGE FORMS AND STRENGTHS
Dosage Form Strengths
Single use vials (preservative-free) 2 mg/0.5 mL, 3 mg/0.5 mL, 4 mg/0.5 mL, 5 mg/0.5 mL, and 6 mg/0.5 mL

Single use pre-filled syringes (preservative-free) 1 mg/0.5 mL, 2 mg/0.5 mL, 3 mg/0.5 mL, 4 mg/0.5 mL, 5 mg/0.5 mL, and 6 mg/0.5 mL

Multiple use vials (with preservative) 10 mg/mL and 20 mg/2 mL

CONTRAINDICATIONS:
Uncontrolled hypertension.
Serious allergic reactions to OMONTYS

WARNINGS AND PRECAUTIONS
Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefits.

Use caution in patients with coexistent cardiovascular disease and stroke.
Hypertension: Control hypertension prior to initiating and during treatment with OMONTYS.