Pegfilgrastim-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEGFILGRASTIM-VISTA (PEGFILGRASTIM-VISTA)

Composition:

Active substance: pegfilgrastim;

1 pre-filled syringe (0.6 mL of injection solution) contains 6 mg of pegfilgrastim;

Excipients: sorbitol (E420), polysorbate 20, sodium hydroxide, glacial acetic acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution, practically free of visible particles.

Pharmacotherapeutic group.

Immunostimulants. Colony-stimulating factors. Pegfilgrastim. ATC code L03A A13.

Immunological and biological properties.

Pharmacodynamics.

Pegfilgrastim is a covalent conjugate of filgrastim (recombinant human granulocyte colony-stimulating factor (G-CSF)) with one molecule of polyethylene glycol (PEG) with a molecular weight of 20 kDa. Human G-CSF is a glycoprotein that regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim exhibits a prolonged effect due to low renal clearance. Pegfilgrastim and filgrastim have the same mechanism of action: both significantly increase the number of neutrophils in peripheral blood within 24 hours and slightly increase the number of monocytes and/or lymphocytes. Similar to filgrastim, neutrophils generated in response to pegfilgrastim therapy demonstrate normal or enhanced functional activity (chemotaxis and phagocytosis).

Like other hematopoietic growth factors, G-CSF may stimulate endothelial cells in vitro. G-CSF is capable of stimulating the growth of myeloid cells, including malignant ones, in vitro. Similar effects are possible regarding certain non-myeloid cells in vitro.

A single administration of pegfilgrastim after each cycle of myelosuppressive cytotoxic therapy reduces the duration of neutropenia and the incidence of febrile neutropenia similarly to daily administration of filgrastim (approximately 11 daily injections on average).

Pharmacokinetics.

After a single subcutaneous administration of pegfilgrastim, its maximum serum concentration is reached within 16–120 hours. The achieved serum concentration of pegfilgrastim is maintained throughout the period of neutropenia following myelosuppressive chemotherapy. The elimination of pegfilgrastim is nonlinear and dose-dependent. The clearance of pegfilgrastim from serum decreases with increasing dose. The clearance of pegfilgrastim is primarily mediated by neutrophils and decreases with increasing pegfilgrastim dose. According to the self-regulating clearance mechanism, the serum concentration of pegfilgrastim rapidly declines with the onset of neutrophil recovery.

Clinical characteristics.

Indications.

To reduce the duration of neutropenia and the incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignant diseases (with the exception of chronic myeloid leukemia and myelodysplastic syndrome).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

The medicinal product should be administered 24 hours after administration of cytotoxic chemotherapeutic agents due to the sensitivity of rapidly dividing myeloid cells to cytotoxic therapy. In clinical studies, pegfilgrastim was safely administered 14 days prior to administration of cytotoxic chemotherapeutic agents. Concomitant administration of pegfilgrastim with chemotherapeutic agents has not been studied in humans. In animal studies, enhanced myelosuppression was observed when pegfilgrastim was administered together with 5-fluorouracil (5-FU) or other antimetabolites. Possible interactions with other hematopoietic growth factors and cytokines have not been studied in clinical trials.

The potential interaction with lithium, which also promotes neutrophil release, has not been specifically investigated; therefore, there is no evidence confirming that such an interaction could be harmful. The safety and efficacy of pegfilgrastim administration in patients receiving chemotherapy associated with delayed myelosuppression, such as nitrosourea compounds, have not been studied.

No specific studies on interactions and effects on metabolism have been conducted; however, according to clinical data, no interactions between pegfilgrastim and other medicinal products have been observed to date.

Special precautions for use.

Monitoring.

To improve tracking of granulocyte colony-stimulating factor (G-CSF) products, the trade name of the administered medicinal product should be clearly documented in the patient's medical record. Limited clinical data suggest comparable effects of pegfilgrastim and filgrastim on the duration of severe neutropenia in patients with de novo acute myeloid leukemia (AML) (see section "Pharmacodynamics"). However, the long-term effects of pegfilgrastim in AML have not been established; therefore, it should be used with caution in this patient population.

Granulocyte colony-stimulating factor may promote the growth of myeloid cells in vitro, and similar effects may be observed in certain non-myeloid cells in vitro. The safety and efficacy of pegfilgrastim have not been studied in patients with myelodysplastic syndrome, chronic myeloid leukemia, or secondary AML; therefore, it should not be administered to such patients. Particular caution should be exercised in differentiating the diagnosis of blast-phase chronic myeloid leukemia from acute myeloid leukemia.

The safety and efficacy of pegfilgrastim in patients under 55 years of age with newly diagnosed AML and t(15;17) cytogenetics have not been established.

The safety and efficacy of pegfilgrastim have not been studied in patients receiving high-dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosing regimens. Pulmonary adverse reactions

Pulmonary adverse reactions, including interstitial pneumonia, have been reported following administration of G-CSF. Patients with recent pulmonary infiltrates or pneumonia may be at higher risk (see section "Adverse reactions"). The onset of pulmonary symptoms such as cough, fever, and dyspnea, in combination with radiological signs of pulmonary infiltrates and worsening pulmonary function along with increasing neutrophil counts, may be early signs of acute respiratory distress syndrome. In such cases, administration of pegfilgrastim should be discontinued and appropriate treatment initiated (see section "Special precautions for use"). Glomerulonephritis

Cases of glomerulonephritis have been reported in patients receiving filgrastim and pegfilgrastim. Typically, glomerulonephritis resolved after dose reduction or discontinuation of filgrastim and pegfilgrastim. Monitoring of urinalysis is recommended. Capillary leak syndrome

Capillary leak syndrome has been reported after administration of G-CSF, characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Patients experiencing symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include intensive care (see section "Adverse reactions").

Splenomegaly and splenic rupture

Cases of usually asymptomatic splenomegaly and cases of splenic rupture, including fatal cases, have been reported after administration of pegfilgrastim (see section "Special precautions for use"). Therefore, spleen size should be carefully monitored (e.g., clinical examination, ultrasound). The diagnosis of splenic rupture should be considered in patients reporting pain in the upper left quadrant of the abdomen or shoulder pain. Thrombocytopenia and anemia

Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anemia, as full-dose myelosuppressive chemotherapy is administered according to the established regimen. Regular monitoring of platelet count and hematocrit is recommended. Particular caution should be exercised when prescribing individual or combination chemotherapeutic agents known to cause severe thrombocytopenia. Myelodysplastic syndrome and acute myeloid leukemia in patients with breast and lung cancer

In post-marketing observational studies, the use of pegfilgrastim in combination with chemotherapy and/or radiotherapy has been associated with the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer (see section "Adverse reactions"). Monitoring of patients with breast and lung cancer for signs and symptoms of MDS/AML is required.

Medication error due to device malfunction

There is a risk of medication error, including administration of a partial dose or failure to receive the full dose of pegfilgrastim, in the event of device malfunction or failure of the internal injector (prefilled syringe). In such cases, the risk of developing neutropenia, febrile neutropenia, and/or infection may be higher than with correct dose administration. Healthcare providers should ensure that patients have received adequate training on the use of the syringe-injector (prefilled syringe) and understand that if a malfunction or device failure is suspected, they should immediately inform a healthcare professional, as a replacement dose may be required.

Sickle cell disease

Sickle cell crisis has been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell anemia (see section "Adverse reactions"). Therefore, physicians should use pegfilgrastim cautiously in patients with sickle cell trait or sickle cell anemia, monitor relevant clinical parameters and laboratory status, and remain vigilant for a possible association between administration of this drug and splenomegaly or vaso-occlusive crisis.

Leukocytosis

Leukocyte counts of 100 × 10⁹/L or higher were observed in less than 1% of patients receiving pegfilgrastim. No reports of adverse events directly related to such levels of leukocytosis were received. This increase in leukocyte count is transient, typically observed 24–48 hours after administration, and corresponds to the pharmacodynamic effects of the medicinal product. Due to the clinical effects and potential for leukocytosis during therapy, leukocyte counts should be monitored at regular intervals. If leukocyte count exceeds 50 × 10⁹/L after the expected nadir, administration of this drug should be discontinued immediately. Hypersensitivity

Cases of hypersensitivity, including anaphylactic reactions, have been reported in patients receiving pegfilgrastim, occurring during initial or subsequent treatment. Permanent discontinuation of pegfilgrastim is recommended in patients with clinically significant hypersensitivity. The medicinal product should not be administered to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be initiated with close monitoring of the patient for several days.

Stevens–Johnson syndrome

Stevens–Johnson syndrome, which may be life-threatening or fatal, has been rarely reported in association with pegfilgrastim treatment. If Stevens–Johnson syndrome develops during treatment with pegfilgrastim, re-administration of pegfilgrastim to that patient is contraindicated.

Immunogenicity

Like all therapeutic proteins, pegfilgrastim has the potential for immunogenicity. The rate of antibody formation against pegfilgrastim is generally low. Antibody binding occurs, as expected, with all biopharmaceuticals; however, such antibodies have not been associated with neutralizing activity to date.

Aortitis

Cases of aortitis have been reported after administration of G-CSF in healthy volunteers and cancer patients. Symptoms observed include fever, abdominal pain, malaise, back pain, and elevated inflammatory markers (e.g., C-reactive protein and leukocyte count). In most cases, aortitis was diagnosed by computed tomography and typically resolved after discontinuation of G-CSF (see section "Adverse reactions"). Other warnings

The safety and efficacy of pegfilgrastim for mobilization of blood progenitor cells in patients or healthy donors have not been adequately evaluated.

The needle cap of the prefilled syringe contains dry natural rubber (a latex derivative), which may cause allergic reactions.

The injector (prefilled syringe) uses acrylic adhesive on the body. In patients with sensitivity to acrylic adhesives, use of this product may lead to allergic reactions.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transiently positive bone imaging results. This should be considered when interpreting bone imaging studies.

Disposal of unused medicinal product or waste

Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out via a "take-back" system if available. Any unused medicinal product or waste must be disposed of in accordance with local requirements.

Important information on excipients

PEGFILGRASTIM-VISTA contains sorbitol. This medicinal product should not be used in patients with hereditary fructose intolerance.

The medicinal product contains less than 1 mmol (23 mg) of sodium per 6 mg dose, i.e., essentially "sodium-free".

Use during pregnancy and breastfeeding.

Pregnancy

There are no adequate data on the use of pegfilgrastim in pregnant women. Reproductive toxicity was observed in animal studies. The potential risk in humans is unknown. Pegfilgrastim is not recommended for use in pregnant women or women of childbearing potential who are not using contraception.

Breastfeeding

There is insufficient information on the excretion of pegfilgrastim/metabolites in human milk; therefore, a risk to newborns/infants cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from pegfilgrastim therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Pegfilgrastim had no effect on reproductive function or fertility in animals at cumulative doses 6–9 times higher than the recommended human dose.

Ability to drive and use machines.

Pegfilgrastim has no effect or has a negligible effect on the ability to drive and use machinery.

Method of Administration and Dosage

Treatment with pegfilgrastim should only be conducted under the supervision of an oncologist and/or hematologist experienced in the use of G-CSF.

The pre-filled syringe containing pegfilgrastim is intended for single use only. The medicinal product is a sterile solution free of preservatives. Before administration, the solution should be visually inspected for the presence of any foreign particulate matter. Only a clear, colorless solution should be administered. Excessive shaking may lead to aggregation of pegfilgrastim, rendering it biologically inactive. Prior to injection, the solution in the pre-filled syringe should be allowed to reach room temperature.

The medicinal product is administered subcutaneously in the thigh, abdomen, or upper arm at a dose of 6 mg (one pre-filled syringe) no sooner than 24 hours after the completion of each cycle of cytotoxic chemotherapy. The medicinal product should not be administered less than 14 days before or earlier than 24 hours after cytotoxic chemotherapy. Instructions for use of the medicinal product

Any unused medicinal product or waste material should be disposed of properly.

Special patient groups

Renal impairment. Dose adjustment is not required for patients with renal impairment, including those with end-stage renal disease.

The medicinal product may be stored at room temperature (not exceeding 30°C) for a maximum single period of up to 72 hours. Any medicinal product left at room temperature for more than 72 hours should be discarded. Do not freeze. Accidental exposure to low temperatures for a single period of less than 24 hours does not adversely affect the stability of pegfilgrastim. Store in the original packaging to protect from light.

Children.

The safety and efficacy of pegfilgrastim in children have not been established.

Overdose

Symptoms. Cases of overdose in humans have not been reported. The maximum safe dose of pegfilgrastim that can be administered as a single or multiple dose has not been determined. Subcutaneous administration of single doses of 300 mcg/kg body weight to a small number of healthy volunteers and patients with non-small cell lung cancer did not result in serious adverse events. Adverse effects were similar to those observed in patients receiving lower doses of pegfilgrastim.

Treatment. In the event of overdose, leukapheresis should be considered.

Adverse reactions.

Summary of safety profile

The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common [≥ 1/100 to < 1/10]). Bone pain was generally mild to moderate, transient, and could be managed in most patients with standard analgesics.

Hypersensitivity reactions, including skin rash, urticaria, angioedema, dyspnea, erythema, flushing, and hypotension, occurred during initial or subsequent treatment with pegfilgrastim (uncommon [≥ 1/1000 to < 1/100]). Serious allergic reactions, including anaphylaxis (uncommon), may occur in patients receiving pegfilgrastim (see section "Special precautions"). Capillary leak syndrome, which may be life-threatening if treatment is delayed, has been reported as an uncommon adverse reaction (≥ 1/1000 to < 1/100) in oncology patients undergoing chemotherapy after administration of G-CSF; see section "Special precautions" and section "Description of selected adverse reactions" below.

Splenomegaly, usually asymptomatic, occurs rarely.

Cases of splenic rupture, including some fatal cases, have been reported rarely following administration of pegfilgrastim (see section "Special precautions").

Uncommon adverse reactions affecting the lungs have been reported, including interstitial pneumonia, pulmonary edema, pulmonary infiltrates, and pulmonary fibrosis. Uncommonly, these cases have led to respiratory failure or acute respiratory distress syndrome, which may be fatal (see section "Special precautions").

Individual cases of sickle cell crisis have been reported in patients with sickle cell trait or sickle cell anemia (uncommon in patients with sickle cell disease) (see section "Special precautions"). List of adverse reactions

The data presented below describe adverse reactions reported during clinical trials and spontaneous reports. Within each frequency category, adverse events are listed in order of decreasing severity.

1 See section "Description of individual adverse reactions" below.

2 This adverse reaction was identified during post-marketing surveillance, but was not observed in randomized controlled clinical trials in adults. The frequency category was estimated based on statistical calculations from data of 1576 patients who received pegfilgrastim in 9 randomized clinical trials.

Description of individual adverse reactions

Rare cases of Sweet’s syndrome have been reported, although in some cases underlying hematological malignancies may have played a contributing role.

Uncommon cases of cutaneous vasculitis have been reported in patients receiving pegfilgrastim. The mechanism of vasculitis development in patients receiving pegfilgrastim is unknown. Injection site reactions, including injection site erythema (uncommon) and injection site pain (common), occurred during initial or subsequent treatment with pegfilgrastim. Injection site reactions (including events such as bleeding, pain, discomfort, bruising, and erythema) have been reported with the use of the on-body injector (prefilled syringe). Contact dermatitis and local skin reactions such as rash, pruritus, and urticaria have been reported during use of the on-body injector (prefilled syringe), which may indicate a hypersensitivity reaction to the adhesive.

Common cases of leukocytosis (white blood cell count > 100 × 10^9/L) have been reported (see section "Special precautions for use").

Reversible, mild to moderate increases in uric acid and alkaline phosphatase levels, without corresponding clinical effects, have been reported rarely; reversible mild to moderate increases in lactate dehydrogenase levels without associated clinical effects were uncommon in patients receiving pegfilgrastim after cytotoxic chemotherapy. Nausea and headache were very common in patients receiving chemotherapy.

Unusual elevations in liver function parameters—alanine aminotransferase or aspartate aminotransferase—have been observed in patients after administration of pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline levels. In an epidemiological study involving patients with breast and lung cancer, an increased risk of developing MDS/AML was observed after treatment with pegfilgrastim in combination with chemotherapy and/or radiotherapy (see section "Special precautions for use"). Common cases of thrombocytopenia have been reported. Cases of capillary leak syndrome have been reported in the post-marketing period with the use of G-CSF. This typically occurs in patients with advanced malignancies, sepsis, those receiving multiple chemotherapeutic agents, or undergoing apheresis (see section "Special precautions for use").

Children.

Experience with the use of pegfilgrastim in children is limited. A higher incidence of serious adverse reactions was observed in children aged 0–5 years (92%) compared to children aged 6–11 years, children aged 12 years and older (67% and 80%, respectively), and adults. The most common adverse reaction was bone pain (see sections "Pharmacodynamics" and "Pharmacokinetics").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at 2 to 8 °C. Keep out of reach of children.

Incompatibilities. The medicinal product must not be mixed with other medicinal products, especially with sodium chloride solutions.

Packaging. 0.6 ml (6 mg) in a prefilled syringe, 1 prefilled syringe in a blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. YTEK Pharma GmbH

Manufacturer's address and place of business.

Gutenbergstrasse 13, Flensburg, Schleswig-Holstein, 24941, Germany