Leigras®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEIGRAS® (LEIGRAS)

Composition:

Active substance: pegfilgrastim;

One pre-filled syringe contains 6 mg of pegfilgrastim;

Excipients: glacial acetic acid, sorbitol (E 420), polysorbate 20, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

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

Pharmacological Properties.

Pharmacodynamics.

Pegfilgrastim is a covalent conjugate of filgrastim (recombinant human granulocyte colony-stimulating factor [G-CSF]) with a single 20 kDa polyethylene glycol (PEG) molecule. Human granulocyte colony-stimulating factor is a glycoprotein that regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim exerts a prolonged effect due to reduced 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 produced in response to pegfilgrastim therapy have normal or enhanced functional activity (chemotaxis and phagocytosis).

Like other hematopoietic growth factors, granulocyte colony-stimulating factor may stimulate endothelial cells in vitro. Granulocyte colony-stimulating factor is capable of stimulating the growth of myeloid cells, including malignant cells, in vitro. Similar effects may be observed with certain non-myeloid cells in vitro.

A single dose of pegfilgrastim administered after each cycle of myelosuppressive cytotoxic chemotherapy reduces the duration of neutropenia and the incidence of febrile neutropenia to a degree comparable to daily administration of filgrastim (approximately 11 daily doses on average).

Pharmacokinetics.

After a single subcutaneous administration of pegfilgrastim, maximum serum concentration is reached within 16–120 hours.

Serum concentrations of pegfilgrastim are maintained throughout the period of neutropenia following myelosuppressive chemotherapy.

Pegfilgrastim elimination is nonlinear and dose-dependent. Serum clearance of pegfilgrastim decreases as the dose increases. The clearance of pegfilgrastim is primarily mediated by neutrophils and decreases with increasing doses of pegfilgrastim.

According to the self-regulating clearance mechanism, serum concentrations of pegfilgrastim rapidly decline with the onset of neutrophil recovery.

Pharmacokinetics in Special Patient Populations

Due to neutrophil-mediated clearance, it is evident that the pharmacokinetics of pegfilgrastim are not altered in renal or hepatic impairment.

Elderly patients (over 65 years of age)

Limited data indicate that the pharmacokinetics of pegfilgrastim in patients over 65 years of age are similar to those in younger adults.

Clinical characteristics.

Indications.

For reducing the duration of neutropenia and the incidence of febrile neutropenia in adult patients receiving cytotoxic chemotherapy for malignancies (with the exception of chronic myeloid leukemia and myelodysplastic syndrome).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic therapy, Leigras**®** should be administered 24 hours after administration of cytotoxic chemotherapeutic agents. In clinical studies, the drug was safely administered 14 days prior to administration of cytotoxic chemotherapeutic agents. Concomitant administration of pegfilgrastim with chemotherapeutic agents in humans has not been studied. In animal studies, administration of pegfilgrastim together with 5-fluorouracil (5-FU) or other antimetabolites resulted in enhanced myelosuppression.

Interactions with other hematopoietic growth factors and cytokines have not been specifically studied in clinical trials.

The potential interaction with lithium, which also promotes neutrophil release, has not been specifically investigated. There is no evidence that this interaction could be harmful.

The safety and efficacy of pegfilgrastim in patients receiving chemotherapy associated with delayed myelosuppression, such as nitrosourea agents, have not been studied.

Specific studies on interactions or effects on metabolism have not been conducted. However, based on clinical trial data, no interactions between pegfilgrastim and other medicinal products have been observed to date.

Special precautions for use.

Traceability

To improve traceability of granulocyte colony-stimulating factor (G-CSF), the trade name of the administered product should be clearly recorded in the patient's medical record.

Limited data indicate that the efficacy of pegfilgrastim and filgrastim is comparable with regard to time to recovery from severe neutropenia in patients with de novo acute myeloid leukemia. However, caution should be exercised when using Leigras**®** in patients with de novo acute myeloid leukemia, as the long-term consequences of such therapy have not been established.

Granulocyte colony-stimulating factor may promote the growth of myeloid and some non-myeloid cells in vitro.

Leigras**®** should not be administered to patients with myelodysplastic syndrome, chronic myeloid leukemia, or secondary acute myeloid leukemia, as the safety and efficacy of the drug have not been studied in these patient groups. Differential diagnosis between blast transformation of chronic myeloid leukemia and acute myeloid leukemia should be performed particularly carefully.

The safety and efficacy of Leigras**®** in patients over 55 years of age with acute myeloid leukemia and t(15;17) translocation have not been established.

The safety and efficacy of Leigras**®** in patients who have received high-dose chemotherapy have not been studied.

Leigras**®** should not be used to increase the dose of cytotoxic chemotherapy beyond the established dosing regimens.

Pulmonary adverse reactions.

Rarely (≥ 1/1000 to <1/100), pulmonary adverse effects, including interstitial pneumonia, have been reported after administration of granulocyte colony-stimulating factor (G-CSF). Patients with a history of pulmonary infiltrates or pneumonia are at increased risk of developing pulmonary adverse effects.

Cough, fever, and dyspnea in combination with radiological infiltrative changes, worsening lung function, and increased neutrophil count may be signs of adult respiratory distress syndrome (ARDS). In such cases, Leigras**®** should be discontinued at the physician’s discretion, and appropriate treatment initiated.

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Typically, manifestations of glomerulonephritis resolve after dose reduction or discontinuation of filgrastim and pegfilgrastim. Monitoring of urine analysis is recommended.

Capillary leak syndrome

Cases of capillary leak syndrome (CLS) have been reported in patients receiving filgrastim and pegfilgrastim, which are recombinant human granulocyte colony-stimulating factors. Symptoms include hypotension, hypoalbuminemia, edema, and hemoconcentration. Patients who develop symptoms of CLS should be closely monitored and provided with standard symptomatic treatment, which may include intensive care if necessary (see section "Adverse reactions").

Splenomegaly and splenic rupture

Asymptomatic cases of splenomegaly have been reported infrequently, and isolated cases of splenic rupture have occurred after pegfilgrastim administration, some of which were fatal. The size of the spleen should be carefully monitored (clinically and by ultrasound). A diagnosis of splenic rupture should be suspected in patients complaining of pain in the upper left quadrant of the abdomen or left shoulder tip.

Thrombocytopenia and anemia

Treatment with Leigras**®** does not prevent the development of thrombocytopenia and anemia during continuation of myelosuppressive chemotherapy at full dose. Platelet count and hematocrit should be monitored regularly. Particular attention should be paid to caution when administering a single chemotherapeutic agent or combination thereof 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. Monitoring of patients with breast and lung cancer for signs and symptoms of MDS/AML is required.

Sickle cell anemia.

Sickle cell crisis has been associated with pegfilgrastim therapy in patients with sickle cell anemia. Physicians should carefully monitor the use of Leigras**®** in patients with sickle cell anemia, monitor relevant clinical and laboratory parameters, and be aware of the possible association between Leigras**®** administration and splenomegaly or vaso-occlusive crisis.

Leukocytosis

Leukocytosis of 100 × 10⁹/L or higher was observed in less than 1% of patients receiving pegfilgrastim. No adverse events directly related to such leukocytosis have been reported. This increase in white blood cell count is transient and typically occurs 24–48 hours after pegfilgrastim administration, consistent with the pharmacodynamic effects of pegfilgrastim. Due to the clinical effect and impact of the drug on white blood cell count, white blood cell counts should be determined at regular intervals during treatment. If the white blood cell count exceeds 50 × 10⁹/L after the expected nadir, this medicinal product should be discontinued immediately.

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions occurring at the initial stage of therapy or during further treatment, have been reported in patients receiving pegfilgrastim. Pegfilgrastim should be discontinued in patients with clinically significant hypersensitivity. The drug should not be administered to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. In the event of a severe allergic reaction, appropriate therapy should be initiated and the patient monitored for several days.

Stevens-Johnson syndrome

Stevens-Johnson syndrome has been reported rarely in patients receiving pegfilgrastim. If Stevens-Johnson syndrome develops in a patient during treatment with Leigras**®**, the drug should be discontinued immediately. If Stevens-Johnson syndrome occurs during pegfilgrastim therapy, pegfilgrastim treatment should never be resumed in that patient in the future.

Aortitis

Cases of aortitis have been reported after G-CSF administration in healthy volunteers and cancer patients. Symptoms include fever, abdominal pain, malaise, back pain, and elevated inflammatory markers (e.g., C-reactive protein and white blood cell count). In most cases, aortitis was diagnosed by computed tomography (CT), and symptoms resolved after discontinuation of G-CSF.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with pegfilgrastim. The level of anti-pegfilgrastim antibodies is generally low. Binding antibodies develop, as expected for all biopharmaceuticals, but to date they have not been associated with neutralizing activity.

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

Other warnings

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

Increased bone marrow hematopoietic activity in response to growth factor therapy leads to transient positive changes in bone imaging, which should be considered when interpreting results.

The product contains sorbitol (E 420). In case of established intolerance to certain sugars, consult a physician before taking this medicinal product.

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of pegfilgrastim in pregnant women. Reproductive toxicity was observed in animal studies.

Leigras**®** should not be used in pregnant women or women of childbearing potential who are not using contraception.

Period of breastfeeding

It is unknown whether pegfilgrastim is excreted in human breast milk; therefore, the risk to the infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from pegfilgrastim therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Pegfilgrastim had no effect on reproductive function or fertility in male and female rats when administered at cumulative weekly doses approximately 6–9 times higher than the recommended human dose (based on body surface area).

Ability to affect reaction speed when driving or operating machinery.

Leigras**®** has no effect or has a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Treatment with the medicinal product Leigras® must be conducted only under the supervision of an oncologist and/or hematologist experienced in the use of G-CSF.

The drug is administered subcutaneously at a dose of 6 mg (one pre-filled syringe) no sooner than 24 hours after each cycle of cytotoxic chemotherapy.

The injection should be administered into the thigh, abdomen, or upper arm.

Special Patient Groups

Pediatric Population. The safety and efficacy of Leigras® in children have not been established. Available data are described in sections “Pharmacodynamics”, “Pharmacokinetics”, and “Adverse Reactions”, but no dosage recommendations can be provided.

Patients with Renal Impairment. Dose adjustment in patients with impaired renal function, including those with end-stage renal disease, is not recommended.

Before administration, visually inspect the Leigras® solution for foreign particulate matter. Only clear, colorless, and particle-free solutions should be used.

Excessive shaking may lead to aggregation of pegfilgrastim, rendering it biologically inactive.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for Use of the Medicinal Product

Step 1: Prepare

A. Remove the pre-filled syringe from its packaging and gather all materials needed for your injection: alcohol swabs, cotton or gauze pad, adhesive bandage, and a sharps disposal container (none of which are included in the package).

For a more comfortable injection, allow the pre-filled syringe to reach room temperature for approximately 30 minutes before injection. Wash your hands thoroughly with soap and water.

Place the new pre-filled syringe and other supplies on a clean, well-lit surface.

Do not attempt to warm the syringe using a heat source such as hot water or a microwave oven.

Do not leave the pre-filled sy游戏副本

Adverse reactions

The most commonly 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 in severity, transient, and manageable with standard analgesics in most patients.

Hypersensitivity reactions, including skin rash, urticaria, angioedema (Quincke's edema), dyspnea, erythema, flushing, and hypotension, were observed at the beginning and during treatment (uncommon, ≥ 1/1000 to < 1/100). Serious allergic reactions, including anaphylaxis, may occur in patients receiving Leigras**®** (uncommon, ≥ 1/1000 to < 1/100).

In oncology patients undergoing chemotherapy, capillary leak syndrome has been reported (uncommon, ≥ 1/1000 to < 1/100) following administration of granulocyte colony-stimulating factor. This syndrome may be life-threatening if not treated promptly.

Splenomegaly occurs uncommonly and is usually asymptomatic.

Splenic rupture, including some fatal cases, has been reported (following pegfilgrastim administration).

There have been reports of uncommon pulmonary adverse reactions, including interstitial pneumonia, pulmonary edema, lung infiltrates, and pulmonary fibrosis. These cases occasionally led to respiratory failure or acute respiratory distress syndrome, which may be fatal.

Isolated cases of sickle cell crises have been observed in patients with sickle cell trait or sickle cell anemia (uncommon in patients with sickle cells).

Table summarizing adverse reactions

The data presented in the table below describe adverse reactions observed in clinical trials and those reported spontaneously. Within each frequency category, adverse events are listed in order of decreasing severity.

1 See section “Description of selected adverse reactions” below.

2 This adverse reaction was identified in the post-marketing period but was not observed in randomized controlled clinical trials in adults. The frequency category was estimated based on statistical calculation using data from 1,576 patients who received pegfilgrastim in nine randomized clinical studies.

Description of selected adverse reactions

Rare cases of Sweet’s syndrome have been reported, although the underlying hematological malignancies may sometimes have been the cause.

Skin vasculitis, with an unknown mechanism of occurrence, has been reported infrequently in patients receiving pegfilgrastim.

Injection site reactions, including erythema (infrequent, ≥ 1/1,000 to < 1/100), and injection site pain (frequent, ≥ 1/1,000 to < 1/10), were observed at the beginning or during treatment with pegfilgrastim.

Leukocytosis (leukocytes > 100 × 10⁹/L) was frequently reported (≥ 1/1,000 to < 1/10).

In patients receiving pegfilgrastim after cytotoxic chemotherapy, transient mild to moderate elevations in uric acid and alkaline phosphatase levels, without any associated clinical effects, as well as reversible mild to moderate elevations in lactate dehydrogenase levels, without any associated clinical effects, were infrequent.

Nausea and headache are very common in patients receiving chemotherapy.

Elevations in ALT or AST levels have been observed infrequently with the use of pegfilgrastim after cytotoxic chemotherapy. These elevations are transient, and transaminase levels usually return to baseline.

An increased risk of developing MDS/AML following treatment with pegfilgrastim in combination with chemotherapy and/or radiotherapy was observed in an epidemiological study involving patients with breast and lung cancer.

Thrombocytopenia has been frequently reported.

Cases of capillary leak syndrome have been reported in the post-marketing period with the use of granulocyte colony-stimulating factor. These cases typically occurred in patients with advanced malignancies, sepsis, those receiving multiple chemotherapy agents, or those who underwent apheresis.

Pediatric population

Experience with the use of the drug in children is limited. A higher incidence of serious adverse reactions has been observed in younger children (0–5 years, 92%) compared to children aged 6–11 and those over 12 years (80% and 67%, respectively) and adults. The most common adverse reactions were bone pain.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare 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.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging to protect from light at a temperature of 2 to 8 °C.

Leigras® may be stored at room temperature (not exceeding 25 °C) for a single maximum period of up to 72 hours. The medicinal product that has been exposed to room temperature for more than 72 hours must not be used.

Do not freeze. A single accidental exposure to temperatures below 0 °C for a period not exceeding 24 hours does not adversely affect the stability of pegfilgrastim.

Keep out of the reach of children.

Incompatibilities. Leigras® must not be mixed with other medicinal products, including sodium chloride solutions.

Packaging.

0.6 mL in a pre-filled syringe.

1 syringe with an injection needle in a blister. 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak" (secondary packaging, quality control, batch release of bulk product manufactured by INTAS PHARMACEUTICALS LTD., India).

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.