Blincito powder concentrate solution for infusion 35 µg+stabilizer,1pcs

Composition

Each bottle of the drug contains: Active ingredient: blinatumomab – 35 mcg; excipients: citric acid monohydrate-3.68 mg, trehalose dihydrate-105.0 mg, lysine hydrochloride-25.58 mg, polysorbate 80-0.70 mg, sodium hydroxide-as much as is required to adjust the pH to 7.0. Each vial of stabilizer solution for infusion preparation contains: citric acid monohydrate-52.5 mg, lysine hydrochloride-2283.8 mg, polysorbate 80-10 mg, sodium hydroxide-qs up to pH 7.0, water for injection-qs up to 10 ml

Pharmacological action

Antitumor drugs, monoclonal antibodies.

ATX code: L01XC19

Pharmacological properties

Pharmacodynamics

Mechanism of action

Blinatumomab is a bispecific T-cell activator (BiTE®) and is an antibody construct that selectively binds to the CD19 antigen expressed on the surface of B cells and the CD3 antigen expressed on the surface of T cells. It activates endogenous T cells by binding CD3 in the T cell receptor (TCR) complex to CD19 on benign and malignant B cells.

The antitumor activity of blinatumomab is cholyclonal in nature and does not depend on human leukocyte antigen (4JIA) molecules on target cells. The formation of a pitolytic synapse between the T cell and the tumor cell mediated by blinatumomab leads to the release of proteolytic enzymes that destroy target cells both in the proliferation stage and at rest. Blinatumomab transiently activates increased expression of cell adhesion molecules, production of cytolytic proteins, release of inflammatory pytokines, and proliferation of T cells, and leads to the elimination of CD 19+cells.

Pharmacodynamic effects

Stable immune pharmacodynamic responses were observed in patients in the studies. During continuous intravenous infusion for 4 weeks, the pharmacodynamic response was characterized by activation and initial redistribution of T cells, rapid elimination of peripheral B cells, and a transient increase in cytokines.

After starting the Blincito infusion or increasing the dose, there was a redistribution of peripheral T cells (i. e., T cell adhesion to the endothelium and / or transmigration to blood vessel tissues). In most patients, T-cell levels initially decreased within 1-2 days, and then returned to baseline within 7-14 days. In some patients, an increase in the number of T cells above the initial level (T cell expansion) was observed.

In most patients, peripheral B cell levels rapidly decreased to undetectable levels during treatment at doses >5 mcg / m / day or >9 mcg/day. There was no recovery in the number of peripheral B cells during the 2-week break between treatment cycles. Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day, and in several non-responders-at higher doses.

Increased concentrations of IL-6,11, -10, and IFN-γ were observed when determining the levels of cytokines IL-2, IL-4. IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ.

A transient increase in cytokines was observed in the first 2 days after the start of the infusion with Blincito. Elevated cytokine levels returned to baseline within 24-48 hours during the infusion. In subsequent treatment cycles, increased cytokines were observed in fewer patients with lower intensity compared to the initial 48 hours of the first treatment cycle.

Immunogenicity

The immunogenicity of Blincito was evaluated using an electrochemiluminescence (ECL) screening immunoassay to detect binding antibodies to blinatumomab. For patients with a positive result in a screening serum immunoassay, an in vitro biological analysis was performed to detect neutralizing antibodies.

In clinical trials,0.9% (2 out of 225) of patients with recurrent or refractory acute lymphoblastic leukemia (ALL) treated with Blincito tested positive for antibodies to blinatumomab; in both cases, the antibodies were neutralizing.

The formation of antibodies to blinatumomab may affect the pharmacokinetics of Blincito. There was no association between the development of antibodies and the development of adverse reactions.

Like all therapeutic proteins, blinatumomab has potential immunogenicity. If neutralizing antibodies are suspected, contact the company’s official representative in the Russian Federation for an antibody test.

Detection of the formation of antibodies to blinatumomab largely depends on the sensitivity and specificity of the assay. In addition, several factors, including the method of analysis, sample handling, sampling time, concomitant medications, and underlying disease, can affect the frequency of a positive response to antibodies (including neutralizing antibodies). For these reasons, comparing the frequency of occurrence of antibodies to blinatumomab with the frequency of occurrence of antibodies to other drugs can be misleading.

Pharmacokinetics

The pharmacokinetics of blinatumomab in adult patients are linear in the dose range from 5 to 90 mcg / m2 / day (approximately equivalent to 9 to 162 mcg / day). After continuous intravenous infusion, the steady-state serum concentration (Css) was reached within 24 hours and remained stable over time. The increase in average Css values was approximately proportional to the dose in the studied dose range. At clinical doses of 9 mcg / day and 28 mcg / day for the treatment of relapsing / refractory ALL, the mean (SD) Css was 211 (258) pg / ml and 621 (502) pg/ml, respectively.

Distribution

The estimated mean (SD) volume of distribution in the terminal phase (Vz) after continuous intravenous infusion of blinatumomab was 4.52 (2.89) liters.

Metabolism

The metabolic pathway of blinatumomab has not been studied. Like other therapeutic proteins, Blincito is expected to degrade into small peptides and amino acids via catabolic pathways.

Deduction

The estimated mean (SD) systemic clearance for continuous intravenous infusion in patients receiving blinatumomab in clinical trials was 2.92 (2.83) l / hr. The mean (SD) elimination half-life was 2.11 (1.42) hours. At the clinical doses tested, small amounts of blinatumomab were excreted in the urine.

Body weight, body surface area, gender, and age

To assess the effect of demographics on the pharmacokinetics of blinatumomab, a population-based pharmacokinetic analysis was performed. The results show that age (7 months to 80 years), gender, body weight (7.5 to 149 kg), and body surface area (0.37 to 2.70 m2 ) do not affect the pharmacokinetics of blinatumomab.

Kidney failure

Formal studies of the pharmacokinetics of blinatumomab in patients with renal insufficiency have not been conducted.

Pharmacokinetic analyses showed an approximately 2-fold difference in the mean clearance of blinatumomab in patients with moderate renal dysfunction and normal renal function. Since there was high variability between patients (CV% to 95.6%) and clearance values in patients with renal insufficiency were mostly within the limits observed in patients with normal renal function, no clinically significant effect of renal function on clinical outcomes is expected.

Drug interactions

The results of an in vitro test in human hepatocytes show that blinatumomab does not affect the activity of CYP450 enzymes.

A transient increase in cytokines may affect the activity of CYP450 enzymes. Based on physiological models of pharmacokinetics (FMFC), the effect of a transient increase in cytokines on the activity of CYP450 enzymes is less than 30% and lasts less than one week; the effect on exposure to sensitive CYP450 substrates is less than 2-fold. Therefore, the increase in cytokines mediated by blinatumomab appears to have a low potential for clinically significant drug interaction.

Special patient groups

Children

When used in children, the pharmacokinetics of blinatumomab in the dose range from 5 to 30 mcg / m2 / day is linear. When used at the recommended doses, the average (SD) Steady-state concentrations (Css) were 162 (179) and 533 (392) pg/ml when administered at doses of 5 and 15 mcg / m2 / day, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL), and elimination half-life (half-life, z) were 3.91 (3.36) l/m2,1.88 (1.90) l/h/m2, and 2.19 (1.53) h, respectively.

Indications

Pre-B-cell Philadelphia chromosome negative recurrent or refractory acute lymphoblastic leukemia (ALL).

Use during pregnancy and lactation

Pregnancy safety and efficacy of Blincito in pregnant women have not been established. No evidence of maternal toxicity, embryotoxicity, or teratogenicity was found in an embryophetal toxicity study conducted in mice using a murine surrogate molecule. In pregnant mice, the expected depletion of B and T cells was observed, but the hematological effects on the fetus were not evaluated. Animal experiments do not always allow extrapolating data to humans. Therefore, it is not known whether the drug Blincito can damage the fetus when administered to a pregnant woman. The use of the drug during pregnancy is contraindicated. Breast-feeding period It is not known whether Blincito is excreted in breast milk.Due to the potential ability of Blincito to cause undesirable effects in infants, the use of Blincito during breastfeeding is contraindicated. Fertility Studies to assess the effect of Blincito on fertility have not been conducted. No effects on the reproductive organs of male or female mice were detected in a 13-week toxicity study with a mouse surrogate molecule.

Contraindications

• Hypersensitivity to blinatumomab or to any component of the drug.
• Severe renal failure.
• Severe liver failure.
• Pregnancy.
• Breast-feeding period.

Side effects

The most serious adverse reactions that may occur during treatment with Blincito include: neurological events, infections, cytokine release syndrome, tumor lysis syndrome, and neutropenia/febrile neutropenia.

The most common adverse reactions (occurring in >20% of patients based on pooled clinical trial data (n=475)) were: hyperthermia, headache, fatigue, nausea, tremor, hypokalemia, diarrhea, and chills.

Adverse reactions are listed below by organ system class and frequency category. Frequency categories were determined by the total frequency coefficient recorded for each adverse reaction in the combined clinical trial data (n=475). In each class of organ systems, adverse reactions are presented in descending order of severity.

ah For more information, see “Description of individual adverse reactions” b MedDRA high-level terminology group (MedDRA version 16.1)

Description of individual adverse reactions

Neurological phenomena

Approximately 50% of patients reported developing one or more neurological adverse reactions (including psychiatric disorders), primarily involving the central nervous system. Serious neurological adverse reactions were observed in less than 20% of patients, of which the most common were encephalopathy, tremor, and confusion. Fatal encephalopathy has been reported, but most neurological events (>90%) were clinically reversible. The median time to onset of the neurological event was 9 days. Clinical control of neurological phenomena.

Infections

Life-threatening or fatal viral, bacterial, and fungal infections have been reported in patients treated with Blincito. In addition, cases of reactivation of viral infection have been observed (for example, John Cunningham (JC) and polioma (VC) viruses). Patients with functional ECOG status >2 experienced a higher incidence of serious infections compared to patients with ECOG status>2. Clinical control of infections.

Cytokine Release Syndrome (SVC)

Serious SVC reactions have been reported in Clinical control of SVC.

Increased liver enzyme concentrations

Approximately 30% of patients reported increased concentrations of liver enzymes. Less than 2% of patients experienced serious adverse reactions, such as increased ALT, increased ACT, and increased bilirubin in the blood. The median time to onset of the first event was 3 days from the start of treatment with Blincito and did not require suspension or discontinuation of treatment with Blincito. Hepatic adverse reactions were generally short in duration and resolved quickly, often with continued continuous infusion of Blincito.

Children’s population

The experience of using it in children is limited. Blincito was evaluated in children with recurrent or refractory ALL from B-cell progenitor cells in a phase I/II dose-escalation/evaluation study. A case of fatal heart failure has been reported with life-threatening cytokine release syndrome (SVS) and tumor lysis syndrome (SLS) when using a dose higher than recommended for adult patients.

Acute lymphoblastic leukemia in children

Adverse reactions in children treated with Blincito were similar to those observed in adult patients. Adverse reactions observed more frequently in the pediatric population compared to the adult population:

Other special populations

Overall, the safety profiles of elderly patients (>65 years) and patients under 65 years of age treated with Blincito were comparable. However, older patients may be more susceptible to serious neurological events, such as cognitive impairment, encephalopathy, and confusion.

Post-registration experience

Life-threatening and fatal adverse events have been reported in patients receiving Blincito.

How to take, course of use and dosage

Hospitalization is recommended for at least the first 9 days of the first cycle and the first 2 days of the second cycle. Starting all subsequent cycles and starting treatment again (for example, if treatment is interrupted for 4 or more hours) should be carried out under the supervision of a doctor or with hospitalization. Infusion bags containing Blincito should be prepared for infusion within 24 hours. 48 hours,72 hours, or 96 hours.

Dosage regimen

Blincito is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump. One treatment cycle is 28 days (4 weeks) of continuous infusion. The cycles are separated by 14-day (2-week) treatment breaks. Patients can receive 2 cycles of induction followed by 3 additional cycles of consolidation.

Recommended daily doses depending on the patient’s weight are shown in Table 1. Patients weighing 45 kg or more receive a fixed dose, for patients weighing less than 45 kg, the dose is calculated based on body surface area (BTA).

Table 1. Recommended doses of Blincito

* One treatment cycle with Blincito is 28 days (4 weeks) of continuous intravenous infusion, followed by a 14-day (2-week) break in use.

Recommendations for premedication and additional drug therapy

Before and during therapy with Blincito, prevention in the form of intrathecal chemotherapy is recommended to prevent relapse of ALL from the central nervous system.

Additional recommendations for premedication are given below:

Preliminary phase of treatment of patients with high tumor load

Dexamethasone should be used in patients with >50% of bone marrow blast cells or with a peripheral blood leukemia blast count of > 15,000/µl (no more than 24 mg / day).

Dose adjustment

If the interruption of treatment due to the development of an adverse event lasted no more than 7 days, the cycle should be resumed until a total of 28 days of infusion is completed, including the days before and after the interruption of this cycle. If the withdrawal of the drug due to the development of an undesirable event lasted more than 7 days, you should start a new cycle.

Based on the General Terminology of Adverse Event Criteria (JTSAE). Grade 3 – severe and Grade 4-life-threatening.

Special instructions for use and handling Note: 1 pack contains 1 bottle of Blincito and 1 bottle of stabilizer solution for infusion preparation.

• Add the stabilizer solution to prepare the infusion solution to a pre-filled infusion bag containing 0.9% sodium chloride solution. The Blincito product package contains an infusion solution stabilizer solution used to coat the pre-filled infusion bag before adding the reconstituted Blincito product to prevent the Blincito product from adhering to the infusion bag and infusion lines.

Before cooking, make sure that the following materials are prepared::

• 1 or more packages of Blincito required for each dose (use 1 package unless otherwise specified below)
  • Patients weighing 45 kg and more
    • than 2 packs of Blincito for the preparation of a dose of 9 mcg / day, infused for 96 hours at a rate of 2.5 ml / h and a dose of 28 mcg / day. infused for 48 hours at a rate of 5 ml / h
    • 3 packs of Blincito to prepare a dose of 28 mcg / day, infused for 72 hours at a rate of 3.3 ml / h
    • 4 packs of Blincito to prepare a dose of 28 mcg / day, infused for 96 hours at a rate of 2.5 ml / h
  • Patients weighing less than 45 kg
    • 2 packages of Blincito are required to prepare a dose of 15 mcg / m2 / day, infused for 48 hours at a rate of 5 ml / hour for patients with a PTA of more than 1.09 m2
    • 3 packages of Blincito are required to prepare a dose of 15 mcg / m2 / day, infused for 72 hours at a rate of 3.3 ml / hour for patients with a BPT greater than 1.39 m2
    • 2 packages of Blincito are required to prepare a dose of 15 mcg / m2 / day, infused for 72 hours at a rate of 3.3 ml / hour for patients with PG1 T from 0.70 m2 to 1.39 m2
    • 3 packages of Blincito are required to prepare a dose of 15 mcg / m2 / day, infused for 96 hours at a rate of 2.5 ml / hour for patients with a PTA greater than 0.99 m2
    • 2 packages of Blincito are required to prepare a dose of 15 mcg / m2 / day, infused for 96 hours at a rate of 2.5 ml / hour for patients with PTA from 0.50 m2 to 0.99 m2

The following materials are also required, but not included in the package:

• Materials for preparation of a 270 ml infusion bag with 0.9% sodium chloride solution
  • Empty infusion bag. Use only infusion bags/pump cassettes made of polyolefin, PVC without diethylhexyl phthalate (without DEHP), or ethylene vinyl acetate (EVL)
  • 0.9% sodium chloride infusion solution (for example,1000 ml)
• Sterile water for injection, without preservatives
• Sterile Disposable Syringes
• Needle (s) size 21 to 23 (recommended)
• Infusion lines made of polyolefin, PVC without DEHP. or EVA with a sterile, non-pyrogenic, built-in 0.2 µm filter with low binding to plasma proteins
  • Make sure that the infusion line is compatible with the infusion pump

Recovery of Blincito and preparation of an infusion package of Blincito

Restoration of the Blincito preparation

Preparation of infusion packs of Blincito preparation

Check the prescribed dose and duration of infusion for each infusion package of Blincito.

Use the specific volumes shown in Tables 2-4 to prepare an infusion package of Blincito to minimize calculation errors.

• Table 2 for patients weighing 45 kg or more
• Tables 3 and 4 for patients weighing less than 45 kg

Table 2. For patients weighing 45 kg or more: volume of 0.9% sodium chloride, stabilizer solution for the preparation of the infusion solution and the reconstituted preparation of Blincito for adding

a 2 pack of the drug Blancato to prepare doses of 9 mg/day, infusional for

96 hours at the rate of 2.5 ml/HR and 28 µg/day, infusional within 48 hours at a rate of 5 ml/hour 3 package Blancato to prepare the dose of 28 µg/day, infusional within 72 hours with a speed of 3.3 ml/hour

with 4 packs of the drug Blancato to prepare the dose of 28 µg/day, infusional for 96 hours at the rate of 2.5 ml/h

Table 3. For patients weighing less than 45 kg: for a dose of 5 mcg / m2 / day, a volume of 0.9% sodium chloride, a stabilizer solution for preparing an infusion solution, and a reconstituted Blincito preparation for adding

Table 4. For patients weighing less than 45 kg: for a dose of 15 mcg / m2 / day, a volume of 0.9% sodium chloride, a stabilizer solution for preparing an infusion solution, and a reconstituted Blincito preparation for adding

and 2 packages of the drug Blancato to prepare the dose of 15 µg/m2/day, infusional within 48 hours at a rate of 5 ml/h for patients with 1II IT more of 1.09 m 2b 3 package Blancato to prepare the dose of 15 µg/m2/day, infusional within 72 hours with a speed of 3.3 ml/hour for patients with PPT more of 1.39 m 2c 2 packages of the drug Blancato to prepare the dose of 15 µg/m 2/day, infusional within 72 hours with a speed of 3.3 ml/hour for patients with PPT 0.70 m 2 – 1,39 m 2d 3 package Blancato to prepare the dose of 15 µg/m2/day, infusional for 96 hours at the rate of 2.5 ml/h for patients with PPT more 0,99 m 2e 2 packages of the drug Blancato to prepare the dose of 15 µg/m2/day, infusional for 96 hours at the rate of 2.5 ml/h for patients with PPT 0.50 m 2 – 0,99 m2

Method of injectingexchange of the infusion bag

The infusion bag should be replaced at least every 24-96 hours by a healthcare professional for sterility reasons.

• Blincito is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump. The infusion pump used to administer the Blincito infusion solution must be programmable, lockable, non-elastomeric, and have an audible alarm.
• Prepared infusion packs of Blincito (see section “Dosage and use”) should be infused within 24 hours,48 hours,72 hours or 96 hours. The duration of the infusion is chosen by the attending physician, taking into account the frequency of replacement of infusion bags.
• The initial volume (270 ml) is larger than the volume administered to the patient (240 ml), to account for refilling the infusion line and ensure that the patient receives the full dose of Blincito.
• Infusion of the Blincito solution should be performed at one of the following constant infusion rates in accordance with the instructions given in the label of the prepared infusion bag:
  • Infusion rate of 10 ml / h for 24 hours
  • Infusion rate of 5 ml / h for 48 hours
  • Infusion rate 3.3 ml / h for 72 hours
  • Infusion rate 2.5 ml / h for 96 hours
• The solution of Blincito for infusions should be administered using an infusion line containing a built-in sterile, pyrogen-free 0.2 µm filter with low protein binding.
• Important note: Do not flush the intravenous Blincito catheter, especially when replacing the infusion bags. Flushing when replacing the infusion bags or at the end of the infusion may lead to overdose and subsequent complications. Infusion of the drug Blincito should be performed through the selected lumen.
• At the end of the infusion, any unused solution of Blincito in the infusion bag and infusion lines should be disposed of in accordance with the requirements of the medical institution.

Recovery and preparation of the infusion solution

It is very important to strictly follow the instructions for preparation (including mixing) and use given in this section to minimize dosage errors (including under-dosage and overdose).

Aseptic cooking

When preparing the infusion solution, the technique of asepsis should be strictly observed, since the vials of Blincito do not contain antimicrobial preservatives. To prevent accidental contamination, prepare the Blincito preparation according to aseptic standards.

Specific mixing instructions are provided for each dose and infusion time. Check the prescribed dose and infusion time of Blincito and determine the appropriate dosage preparation section listed below. Follow the instructions for restoring

Blincito and preparing the infusion pack.

Special patient groups

Advanced age

Dose adjustment in elderly patients (>65 years) not required. There is limited experience in patients >75 years of age.

Patients with renal insufficiency

Based on pharmacokinetic analysis, no dose adjustment is required in patients with mild to moderate renal dysfunction. The safety and efficacy of Blincito have not been studied in patients with severe renal insufficiency. Blincito is contraindicated in patients with severe renal insufficiency.

Patients with hepatic insufficiency

Based on the pharmacokinetic analysis, no effect of baseline liver function on exposure to blinatumomab is expected, and no initial dose adjustment is required in patients with mild to moderate hepatic dysfunction. The safety and efficacy of Blincito have not been studied in patients with severe hepatic insufficiency. Blincito is contraindicated in patients with severe hepatic insufficiency.

Incompatibility

Blincito is compatible with infusion bags/pump cassettes made of polyolefin, PVC without diethylhexyl phthalate (not DEHP), or ethylene vinyl acetate (EVA).

Overdose

Cases of overdose have been reported, including one patient who received 133 times the recommended therapeutic dose of Blincito administered over a short period of time. Overdose caused undesirable reactions consistent with those observed at the recommended therapeutic dose, which include hyperthermia, tremor, and headache. In case of overdose, the infusion should be temporarily suspended and the patient should be monitored. After the symptoms resolve, the question of re-starting the use of Blincito at the correct therapeutic dose is considered.

Special instructions

Neurological phenomena

Neurological events have been reported in patients receiving Blincito. Neurological events of grade 3 or higher (severe or life-threatening) after the start of Blincito use included encephalopathy, seizures, speech disorders, impaired consciousness, confusion and disorientation, coordination and balance disorders. The median time to onset of a neurological event was 9 days, with most events resolved and infrequently requiring discontinuation of Blincito. Some phenomena have led to a fatal outcome.

Experience with the use of Blincito in patients with a history of neurological events is limited.

Patients receiving Blincito should be clinically monitored for signs and symptoms of neurological events. Monitoring of these signs and symptoms may require temporary suspension or discontinuation of Blincito therapy.

Infections

Patients with ALL have a weakened immune system and are therefore at an increased risk of serious infections. Patients receiving Blincito have experienced serious infections, including sepsis, pneumonia, bacteremia, opportunistic infections, and infections at the catheter site, some of which were life-threatening or fatal.

Patients with functional ECOG status>2 showed a higher incidence of serious infections compared to patients with ECOG status> Experience with the use of Blincito in patients with active uncontrolled infection is limited.

Patients should be monitored for signs and symptoms of infection, and treated appropriately. Infection control may require temporary suspension or complete discontinuation of Blincito therapy.

The preparation of Blincito should be prepared by personnel with adequate experience in aseptic handling and mixing of cancer drugs. Aseptic procedures should be strictly followed when preparing the infusion solution and performing routine catheter maintenance.

Cytokine release syndrome

Cytokine release syndrome (SVC), which can be life-threatening or fatal, has been reported in patients receiving Blincito.

Serious adverse events that may be associated with SVC. These include hyperthermia, asthenia, headache, increased blood pressure, increased total bilirubin, and nausea; these events have rarely led to discontinuation of Blincito therapy. In some cases, disseminated intravascular coagulation syndrome (DIC), increased capillary permeability syndrome (SPPC), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HPH/CAM) have been reported with SVC. Patients should be carefully monitored for signs and symptoms of these phenomena.

To reduce the risk of SVC, it is important to start treatment with Blincito (cycle 1, days 1-7) at the recommended starting dose indicated in Table 1. SVC control may require temporary suspension or complete discontinuation of Blincito therapy.

Infusion reactions

Infusion reactions may be clinically indistinguishable from manifestations of cytokine release syndrome (SVC).

Patients should be carefully monitored for the occurrence of infusion reactions, especially during the first infusion of the first cycle, and appropriate treatment should be provided. Monitoring of infusion reactions may require temporary suspension or complete discontinuation of Blincito therapy.

Tumor lysis syndrome

Patients receiving Blincito have experienced tumor lysis syndrome (SLS), which can be life-threatening or fatal.

Appropriate preventive measures, including hydration, should be taken to prevent CF during treatment with Blincito. Patients should be carefully monitored for signs or symptoms of CF. Control of these events may require temporary suspension or complete discontinuation of Blincito therapy.

Neutropenia and febrile neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been reported in patients receiving Blincito. Laboratory parameters (including, but not limited to, the number of white blood cells and the absolute number of neutrophils in the blood) should be monitored during the infusion of Blincito and treated accordingly.

Application Errors

During treatment with Blincito, errors in the use of the drug were noted. It is very important to strictly follow the instructions for preparation (including mixing) and use to minimize application errors (including insufficient dose and overdose).

Increased concentration of liver enzymes

Treatment with Blincito was associated with transient increases in liver enzyme concentrations. Most of these events occurred within the first week of starting Blincito and did not require suspension or discontinuation of Blincito therapy.

Blood concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyl transferase (GGT), and total bilirubin should be monitored before and during treatment with Blincito.

Pancreatitis

Life-threatening or fatal cases of pancreatitis have been reported in clinical trials and post-marketing experience in patients receiving Blincito. In some cases, high-dose steroid therapy may contribute to the development of pancreatitis.

Patients who have developed symptoms of pancreatitis should be monitored. Treatment of pancreatitis may require temporary suspension or discontinuation of Blincito.

Leukoencephalopathy

In patients receiving Blincito, changes in the magnetic resonance imaging (MRI) of the skull have been observed indicating leukoencephalopathy, especially in patients with previous radiation therapy of the head and anti-leukemic chemotherapy (including high doses of systemic methotrexate or intrathecal cytarabine). The clinical significance of these changes on MRI is unknown.

Special patient groups

Children

Safety and efficacy were studied in children with recurrent or refractory ALL from B-cell progenitor cells, Philadelphia chromosome negative identified.

In an open-label study of 93 patients,70 patients (aged 7 months to 17 years) received the recommended dose. For each treatment cycle, Blincito was administered as a continuous intravenous infusion for 28 days (4 weeks), followed by a 14-day (2-week) break in treatment.

Blincito was administered at a dose of 5 mcg / m2 / day on days 1 to 7 (week 1) and 15 mcg/m2/day on days 8 to 28 (week 2 to 4) of cycle 1; and 15 mcg/m2/day on days 1 to 28 in subsequent cycles.

In the dose assessment phase of the study,1 patient had a fatal case of cardiac arrest against the background of life-threatening cytokine release syndrome (SVC) and tumor lysis syndrome (SLO) at a dose of 30 mcg/m2/day (above the maximum tolerated/recommended).

Elderly people

In general, safety and efficacy were similar in elderly patients (>65 years) treated with Blincito and in patients under 65 years of age. However, older patients may be more susceptible to serious neurological events, such as cognitive impairment, encephalopathy, and confusion.

Liver failure

Formal pharmacokinetic studies of the use of Blincito in patients with hepatic insufficiency have not been conducted.

Kidney failure

No formal pharmacokinetic studies have been conducted on the use of Blincito in patients with renal insufficiency.

Influence on the ability to drive vehicles and mechanisms

Studies of the effect of the drug Blincito on the ability to drive vehicles and mechanisms have not been conducted. However, due to the possibility of neurological events in patients treated with Blincito, during treatment, you should refrain from driving, participating in dangerous professional or other activities, such as operating heavy or potentially dangerous equipment. Patients should be notified of possible neurological reactions.

Storage conditions

Store at a temperature of 2 to 8°C in the original packaging to protect from light. Do not freeze it. Keep out of reach of children!After opening the package, the maximum storage time for a bottle of Blincito powder and a stabilizer solution for preparing an infusion solution* at a temperature of 23°C to 27°C is 8 hours. The maximum storage time of a vial of reconstituted solution of Blincito * at a temperature of 23°C to 27°C is 4 hours; from 2°C to 8°C-24 hours. The maximum storage time of a prepared infusion bag containing a solution of Blincito for infusions * * at a temperature of 23°C to 27°C is 96 hours* ; at a temperature of 2°C to 8°C – 10 days. * Store vials of Blincito powder and stabilizer solution for infusion preparation in a place protected from light. ** Storage time includes infusion time. If the infusion bag containing the solution of Blincito for infusions is not used within the specified time and at the specified temperatures, it must be disposed of; re-cooling in the refrigerator is not allowed.

Shelf

life is 3 years and 6 months. Do not use after the expiration date.

Active ingredient

Blinatumomab

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution