Filgrastim Contraindications and Side Effects

Filgrastim Contraindications and Side Effects

Filgrastim Contraindications and Side Effects/Filgrastim is a recombinant, non-pegylated human granulocyte colony-stimulating factor (G-CSF) analog. It is marketed as the brand name Neupogen by Amgen (initially approved in 1998) and as Nivestym, a biosimilar agent by Pfizer. Nivestym was approved by the FDA on July 20th, 2018 [rx]. Between 1998 and the present, Neupogen/filgrastim has been approved for various indications [rx].

Filgrastim was approved in the US in 1991 and is the originator of 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.

Mechanism of Action of 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%.

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As a G-CSF analog, this drug controls the proliferation of committed progenitor cells and influences their maturation into mature neutrophils. Filgrastim also stimulates the release of neutrophils from bone marrow storage pools and decreases their time to maturation. Filgrastim acts to increase the phagocytic activity of mature neutrophils, thus allowing them to prevent infection. In patients receiving cytotoxic chemotherapy, filgrastim may accelerate neutrophil recovery, leading to a reduction in the duration of the neutropenic phase post-chemotherapy.

Used in the treatment of chemotherapy-induced neutropenia by enhancing the production of neutrophils, filgrastim acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. In one efficacy study, levels of neutrophils returned to baseline by 21 days following completion of chemotherapy and the administration of tbo-filgrastim (fast-acting) [rx].

Indications of Filgrastim

FDA indications
  • Reduction of the incidence of infection manifested by febrile neutropenia in patients receiving myelosuppressive chemotherapy.
  • Minimizing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML.
  • Shortening the duration of neutropenia and neutropenia-related clinical sequelae in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation.
  • To mobilize hematopoietic progenitor cells to the peripheral blood for collection by leukapheresis in patients undergoing peripheral blood progenitor cell collection and therapy.
  • Chronic administration to lower the incidence and duration of the sequelae of neutropenia in patients with severe chronic neutropenia.
  • Reduction of the duration and severity of neutropenia in patients with radiation-induced myelosuppression following a radiological/nuclear incident (hematopoietic syndrome of acute radiation syndrome, or H-ARS). – This was the only indication where only animal trials were conducted due to ethical and feasibility considerations.
  • Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differientation and survival of cells along the neutrophilic lineage. In addition it may function in some adhesion or recognition events at the cell surface.
  • Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.
Non-FDA indications
  • Alcoholic hepatitis
  • Anemia in myelodysplastic patients
  • Neutropenia in HIV patients
  • Neutropenia in kidney transplant recipients
  • Neutropenia in hepatitis C patients undergoing treatment
  • Clozapine induced neutropenia

Contraindications of Filgrastim

Filgrastim is contraindicated in patients with allergic reactions to E. coli-derived proteins, filgrastim, or any component of the product.

  • sickle cell anemia
  • high levels of white blood cells
  • inflammation of blood vessels in the skin
  • capillary leak syndrome
  • a condition where fluid leaks out of small blood vessels
  • acute respiratory distress syndrome
  • a type of lung disorder
  • glomerulonephritis
  • a condition that affects the kidneys
  • rupture of the spleen
  • aortitis
  • bleeding in the alveoli of the lungs
  • Allergies to Colony Stimulating Factors
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Dosage of Filgrastim

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.

This increase in neutrophil counts was seen whether filgrastim was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous (SC) infusion (3 to 11 mcg/kg/day). After the discontinuation of filgrastim therapy‚ neutrophil counts returned to baseline in most cases within only 4 days after Nevistym was used.

IV compatibility
  • Compatible: 5% dextrose; 5% glucose; 5% dextrose plus albumin (human); 5% glucose plus albumin (human)
  • Incompatible: Saline

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:

  • When ANC >1000/mm^3 for 3 consecutive days: reduce to 5 mcg/kg/day
  • If ANC >1000/mm^3 for an additional 3 or more consecutive days: Discontinue this drug.
  • Then if, ANC < 1000/mm^3: resume at 5 mcg/kg/day

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. 

Congenital Neutropenia
  • The recommended starting dose is 6 mcg/kg BID via subcutaneous injection.
Cyclic/Idiopathic Neutropenia
  • Recommended starting dose is 5 mcg/kg once a day
 In the severe chronic neutropenia post-marketing surveillance study, the median daily dose was
  • Congenital neutropenia: 6mcg/kg
  • Cyclic neutropenia: 2.1 mcg/kg
  • Idiopathic neutropenia: 1.2 mcg/kg

Doses administered via subcutaneous injection

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Patients with Radiation-Induced Neutropenia
  • 10 mcg/kg via subcutaneous injection once a day.
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.

Side Effects

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 Most Common
  • Cancer patients receiving myelosuppressive therapy – Arthralgia, back pain, bone pain, nausea, chest pain, fatigue, pyrexia, dizziness, cough, dyspnea, rash, thrombocytopenia, elevated LDH, elevated alkaline phosphatase.
  • AML patients receiving induction/consolidation chemotherapy – Back pain, pain in extremity, erythema, maculopapular rash, epistaxis. In patients with sequelae of underlying malignancy/ cytotoxic chemotherapy- Diarrhea, constipation, transfusion reaction.
  • Patients with non-myeloid malignancies undergoing myeloablative therapy following Bone Marrow Transplantation (BMT) – Rash, hypersensitivity. In patients receiving intensive chemotherapy followed by autologous BMT – hypertension, sepsis, bronchitis, insomnia, anemia, thrombocytopenia.
  • Patients undergoing peripheral blood progenitor collection and therapy– Headache, bone pain, pyrexia, elevated alkaline phosphatase.
  • Patients with severe chronic neutropenia – arthralgia, back pain, bone pain, muscle spasms, pain in extremity, chest pain, diarrhea, alopecia, epistaxis, hypoesthesia, splenomegaly, anemia Although total infection rates were significantly lower in filgrastim treated patients, the incidence of upper respiratory tract infection and urinary tract infections was higher compared to placebo.
Common

Other adverse effects reported since filgrastim’s approval are as follows-

  • Aortitis
  • Capillary leak syndrome
  • Cutaneous vasculitis
  • Decreased bone density/Osteoporosis
  • Glomerulonephritis
  • Leukocytosis
  • Pulmonary toxicity – ARDS, alveolar hemorrhage/Hemoptysis
  • Severe allergic reactions including anaphylaxis
  • Sickle Cell disorders – severe sickle cell crisis has been reported in some filgrastim-treated sickle cell patients
  • Splenomegaly/Splenic rupture – Filgrastim-treated patients with symptoms of abdominal pain, especially LUQ, require evaluation. 
  • Sweet syndrome 
Rare
  • fever, tiredness, stomach pain, back pain
  • rapid breathing, feeling short of breath, pain while breathing;
  • capillary leak syndrome – sudden dizziness or light-headed feeling, tiredness, trouble breathing, swelling or puffiness and feeling full;
  • kidney problems – little or no urinating, blood in your urine, swelling in your face or ankles;
  • low red blood cells (anemia) – pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet; or
  • signs of infection – fever, chills, sore throat, flu symptoms, easy bruising or bleeding (nosebleeds, bleeding gums), loss of appetite, nausea and vomiting, mouth sores, unusual weakness.
  • fever, cough, trouble breathing;
  • nosebleeds;
  • bone pain, muscle or joint pain;
  • diarrhea;
  • headache;
  • numbness; or
  • rash, thinning hair.

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.

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Drug Interactions

Filgrastim may interact with following drugs, supplement and may change the efficacy of drugs

  • Acetylsalicylic Acid (aspirin)
  • Adrenalin (epinephrine)
  • Adriamycin (doxorubicin)
  • Aloprim (allopurinol)
  • B Complex 100 (multivitamin)
  • Bactrim (sulfamethoxazole / trimethoprim)
  • bleomycin
  • Calcium 600 D (calcium / vitamin d)
  • Cipro (ciprofloxacin)
  • Co-trimoxazole (sulfamethoxazole / trimethoprim)
  • Combivent (albuterol / ipratropium)
  • Demerol (meperidine)
  • Heparin Sodium (heparin)
  • Lasix (furosemide)
  • Mycostatin (nystatin)
  • Paracetamol (acetaminophen)
  • pegfilgrastim
  • Phenytoin Sodium (phenytoin)
  • Plavix (clopidogrel)
  • Rituxan (rituximab)
  • Valproate Sodium (valproic acid)
  • Vitamin D3 (cholecalciferol)

Pregnancy And Lactation

  • The drug is pregnancy category C.

Pregnancy

  • 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.

Monitoring

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:

  • Twice weekly in cancer patients on myelosuppressive therapy or AML patients receiving induction/consolidation therapy.
  • Frequently in bone marrow transplant patients.
  • After four days of filgrastim initiation in patients undergoing PBPC collection and discontinued if neutrophil count >100,000/mm^3.
  • During the initial four weeks of filgrastim therapy and the two weeks following any adjustment in the dose in patients with severe chronic neutropenia

    • When a patient is clinically stable, counts should be monitored monthly in the first year and less frequently thereafter.
  • Every three days until ANC>1000/mm^3 for three consecutive CBCs in patients acutely exposed to myelosuppressive radiation doses.

It is advised not to use filgrastim with concurrent chemotherapy and radiotherapy due to a lack of safety and efficacy studies.

References

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