Lipegfilgrastim – Uses, Dosage, Side Effects, Interaction

Lipegfilgrastim – Uses, Dosage, Side Effects, Interaction

Lipegfilgrastim is a long-acting glycol-pegylated recombinant form of human granulocyte colony-stimulating factor (G-CSF), with hematopoietic activity. Similar to G-CSF, pegfilgrastim binds to and activates specific cell surface receptors, and stimulates neutrophil progenitor proliferation and differentiation. Therefore, this agent may prevent the duration and incidence of chemotherapy-induced neutropenia. Compared to filgrastim, pegfilgrastim has a prolonged plasma half-life.

Pegfilgrastim is a pegylated granulocyte colony-stimulating factor that is FDA-approved to decrease the risk of patients developing febrile neutropenia when receiving myelosuppressive chemotherapy regimens.

Pegfilgrastim is a PEGylated form of the recombinant human granulocyte colony-stimulating factor (G-CSF) analog, filgrastim.[rx] It is used to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid cancer receiving myelosuppressive anti-cancer treatment. Some patients with greater risk factors may develop febrile neutropenia from myelosuppressive therapy and are susceptible to an increased risk of developing infections. Although the risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens,[rx] infections pose risks of hospitalization and mortalities.[rx] Due to the relatively short circulating half-life of filgrastim, a 20 kDa PEG moiety was covalently conjugated to the N-terminus of filgrastim (at the methionine residue) to develop a longer-acting version of the drug.[rx] Due to a longer half-life and slower elimination rate than filgrastim, pegfilgrastim requires less frequent dosing than filgrastim. However, pegfilgrastim retains the same biological activity as filgrastim and binds to the same G-CSF receptor to stimulate the proliferation, differentiation, and activation of neutrophils.[rx]

Mechanism of Action of Lipegfilgrastim

Neutrophils are short-lived immune cells that are highly susceptible to cell death following myelosuppressive chemotherapy. This marked reduction in neutrophil numbers during chemotherapy increases the risk of hospitalization, infection, and infection-related mortality. It also directly impacts the clinical outcome of patients if cases of febrile neutropenia require dose reductions or schedule delay of chemotherapy, thus reducing the clinical efficacy of chemotherapy and patient benefit from receiving appropriate treatment.[rx]

G-CSF is an endogenous hematopoietic growth factor that stimulates granulopoiesis cells of the neutrophil lineage. Pegfilgrastim mimics its biological actions and binds to the same G-CSF receptor expressed on cells of the myeloid lineages, such as granulocytic precursors and mature neutrophils.[rx] Upon binding of the ligand, G-CSF receptor undergoes a conformational change and activates several downstream signaling pathways including JAK/STAT, PI3K/AKT, and MAPK/ERK.[rx] These pathways work to increase the proliferation and differentiation of granulocyte progenitor cells, induce maturation of the progenitor cells, and enhance the survival and function of mature neutrophils.[rx]

Indications of Lipegfilgrastim

  • Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).
  • Prevention of chemotherapy-induced febrile neutropenia, Treatment of chemotherapy-induced neutropenia
  • Previous chemotherapy or radiation therapy
  • Preexisting neutropenia or bone marrow involvement with a tumor
  • Infection
  • Open wounds or undergoing recent surgery
  • Poor performance or nutritional status
  • Impaired renal function
  • Inadequate liver function, mainly indicated by elevated bilirubin
  • Cardiovascular disease
  • Multiple comorbid conditions
  • HIV

It is important to note that the risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens. Therefore, it is essential to make individualized, patient-based decisions when deciding if the use of a granulocyte-colony-stimulating factor is required.

Pegfilgrastim is also FDA-approved to help increase the survival of patients exposed to myelosuppressive doses of radiation. Receiving acute myelosuppressive doses of radiation is a syndrome known as acute radiation syndrome, and pegfilgrastim’s indication is for the hematopoietic sub-syndrome.

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Contraindications of Lipegfilgrastim

  • Sickle cell anemia
  • Pain crisis in sickle cell disease
  • 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
  • Allergies to Colony Stimulating Factors

Dosage of Lipegfilgrastim

Febrile Neutropenia
  • 6 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Comment: Do not administer between 14 days before and 24 hours after the administration of cytotoxic chemotherapy.
Neutropenia Associated with Chemotherapy
  • 6 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
Neutropenia Associated with Radiation
  • 6 mg subcutaneously once a week
  • Duration of treatment: 2 weeks
Pediatric Dose for Febrile Neutropenia
Pediatric patients
  • Bodyweight less than 10 kg – 0.1 mg/kg subcutaneously once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 10 to 20 kg – 1.5 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 21 to 30 kg – 2.5 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 31 to 44 kg – 4 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 45 kg or greater – 6 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
Pediatric Dose for Neutropenia Associated with Chemotherapy

Pediatric patients

  • Bodyweight less than 10 kg – 0.1 mg/kg subcutaneously once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 10 to 20 kg – 1.5 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 21 to 30 kg – 2.5 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 31 to 44 kg –  4 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy
  • Bodyweight 45 kg or greater – 6 mg subcutaneously ONCE per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy.

Side Effects of Lipegfilgrastim

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 were higher compared to placebo.
Common

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

  • Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • blisters in the skin
  • blood in the urine
  • cloudy urine
  • decrease in how much or how often you urinate
  • difficulty with swallowing
  • dizziness
  • fainting or lightheadedness
  • fast heartbeat
  • flushing or redness of the skin
  • hives or welts, skin rash
  • itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • nausea
  • sores on the skin
  • stomach pain
  • swelling of the hands, ankles, feet, or lower legs
  • unusual tiredness or weakness
  • unusually warm skin
  • chest pain
  • difficult or labored breathing
  • eye pain
  • a general feeling of illness
  • headache
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More common
  • Belching
  • change in sense of taste
  • constipation
  • cracked lips
  • diarrhea
  • hair loss or thinning of the hair
  • heartburn
  • indigestion
  • joint pain
  • lack or loss of strength
  • loss of appetite
  • muscle soreness
  • swelling or inflammation of the mouth
  • trouble sleeping
  • vomiting
  • weakness, generalized
  • weight loss
Rare
  • fever, tiredness, stomach pain, back pain
  • rapid breathing, feeling short of breath, pain while breathing;
  • capillary leak syndrome – sudden dizziness or a 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.

Drug Interactions of Lipegfilgrastim

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

  • abemaciclib
  • acalabrutinib
  • aldesleukin
  • alemtuzumab
  • altretamine
  • arsenic trioxide
  • asparaginase escherichia coli
  • avapritinib
  • axicabtagene ciloleucel
  • azacitidine
  • belantamab mafodotin
  • belinostat
  • bendamustine
  • bevacizumab
  • bexarotene
  • bleomycin
  • blinatumomab
  • bortezomib
  • bosutinib
  • brentuximab
  • brexucabtagene auto excel
  • busulfan
  • cabazitaxel
  • capecitabine
  • carboplatin
  • carfilzomib
  • carmustine
  • chlorambucil
  • cisplatin
  • cladribine
  • clofarabine
  • copanlisib
  • cyclophosphamide
  • cytarabine
  • dacarbazine
  • dactinomycin
  • daratumumab
  • dasatinib
  • daunorubicin
  • daunorubicin liposomal
  • decitabinedinutuximab
  • docetaxel
  • doxorubicin
  • doxorubicin liposomal
  • duvelisib
  • enfortumab vedotin
  • epirubicin
  • eribulin
  • etoposide
  • fam-trastuzumab
  • deruxtecan
  • floxuridine
  • fludarabine
  • fludeoxyglucose f18
  • fluorouracil
  • gemcitabine
  • gemtuzumab
  • hydroxyurea
  • ibritumomab
  • ibrutinib
  • idarubicin
  • idelalisib
  • ifosfamide
  • imatinib
  • inotuzumab ozogamicin
  • interferon alfa-2a
  • interferon alfa-2b
  • interferon alfa-n1
  • interferon alfacon-1
  • interferon gamma-1b
  • iobenguane I 131
  • iodine i 131 tositumomab
  • irinotecan
  • irinotecan liposomalisatuximab
  • ixabepilone
  • ixazomib
  • lenalidomide
  • levamisole
  • lithium
  • lomustine
  • lurbinectedin
  • mechlorethamine
  • melphalan
  • mercaptopurine
  • methotrexate
  • midostaurin
  • mitomycin
  • mitoxantrone
  • nelarabine
  • nilotinib
  • niraparib
  • obinutuzumab
  • ofatumumab
  • olaparib
  • omacetaxine
  • osimertinib
  • oxaliplatin
  • paclitaxel
  • paclitaxel protein-bound
  • palbociclib
  • panobinostat
  • pazopanib
  • pegaspargase
  • peginterferon alfa-2a
  • peginterferon alfa-2b
  • pegloticase
  • pegvaliase
  • pemetrexed
  • pentostatin
  • plicamycin
  • polatuzumab vedotin
  • pomalidomide
  • ponatinib
  • pralatrexate
  • procarbazine
  • ribociclib
  • rituximab
  • romidepsin
  • rucaparib
  • ruxolitinib
  • sacituzumab govitecan
  • selinexor
  • streptozocintafasitamab
  • talazoparib
  • temozolomide
  • teniposide
  • thalidomide
  • thioguanine
  • thiotepa
  • tisagenlecleucel
  • topotecan
  • tositumomab
  • trabectedin
  • trastuzumab
  • trimetrexate
  • uracil mustard
  • vinblastine
  • vincristine
  • vincristine liposom
  • vinorelbine
  • zanubrutinib

Pregnancy and Lactation of Lipegfilgrastim

Pregnancy
  • This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, stop taking it immediately and call your doctor.
Breast-feeding
  • It is not known whether pegfilgrastim passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding. The safety and effectiveness of pegfilgrastim have not been established for children.
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Precautions

  • Before starting pegfilgrastim treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, products containing aspirin unless your doctor specifically permits this.
  • The manufacturer recommends that the first dose of pegfilgrastim be given no sooner than 24 hours after chemotherapy.  Your doctor will discontinue therapy with pegfilgrastim when your white blood cell count has reached acceptable levels.
  • Pegfilgrastim may be inadvisable if you have had a hypersensitivity (allergic) reaction to filgrastim, pegfilgrastim or E. coli-derived proteins.
  • Do not receive any kind of immunization or vaccination without your doctor’s approval while taking pegfilgrastim.
  • Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment.  Pregnancy category C (use in pregnancy only when benefit to the mother outweighs risk to the fetus).
  • For both men and women: Do not conceive a child (get pregnant) while taking pegfilgrastim. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.
  • Do not breastfeed while taking this medication.
  • Pegfilgrastim should be used with caution in people taking lithium.

Self-Care Tips

  • If you are performing your own subcutaneous self-injections, remove the syringe from the refrigerator 30 minutes prior to injection.  This will reduce local stinging at the injection site.
  • You may experience bone or joint pain as a result of this medication. Ask your healthcare provider if you may take mild pain medicine to relieve this.  Acetaminophen (Tylenol®) may help.
  • Apply a warm compress if you have any pain, redness or swelling at the injection site, and notify your doctor.
  • You may be at risk of infection so try to avoid crowds or people with colds, and report fever or any other signs of infection immediately to your health care provider.
  • Wash your hands often.
  • Avoid contact sports or activities that could cause injury.
  • This medication causes little nausea. But if you should experience nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals. Sucking on lozenges, and chewing gum may also help.
  • In general, drinking alcoholic beverages should be kept to a minimum or avoided completely.  You should discuss this with your doctor.
  • Get plenty of rest.
  • Maintain good nutrition.
  • If you experience symptoms or side effects, be sure to discuss them with your health care team.  They can prescribe medications and/or offer other suggestions that are effective in managing such problems.

References

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