Blincito, 35 mcg + stabilizer

Indications

Active ingredient

Composition

Each bottle of the drug contains:

Active ingredient:blinatumomab – 35 µg*;
Auxiliary substances: citric acid monohydrate – 3.68 mg, trehalose dihydrate – 105.0 mg, lysine hydrochloride – 25.55 mg, polysorbate 80 – 0.70 mg, sodium hydroxide – to pH 7.0.

Each bottle of stabilizer solution for preparation of solution for infusion contains: citric acid monohydrate – 52.5 mg, lysine hydrochloride – 2283.8 mg, polysorbate 80 – 10 mg, sodium hydroxide – to pH 7.0, water for injection – to 10 ml.
* rated volume of blinatumomab; to extract 35 µg blinatumomab an excess of 38.5 µg is taken.

How to take, the dosage

Treatment must be initiated by and under the supervision of a physician experienced in the treatment of hematologic malignancies.

In order to initiate therapy for relapsed or refractory ALL, hospitalization for a minimum of the first 9 days of the first cycle and the first 2 days of the second cycle is recommended.

The treatment of Philadelphia chromosome-negative VLF-derived precursor OLL with MOB recommends hospitalization for at least the first 3 days of the first cycle of therapy and the first 2 days of subsequent cycles.

Child patients with a first relapse of high risk B-lymphocyte precursor OLL are recommended to be hospitalized for at least the first 3 days of the therapy cycle.

For patients with a history of or currently clinically significant central nervous system (CNS) pathology (see

Hospitalization is recommended for at least the first 14 days of the first cycle and at least 2 days of the second cycle of therapy (the length of hospitalization required is clinically assessed depending on the tolerability of Blincito during the first cycle of therapy). Caution should be exercised as delayed first-onset neurologic disorders have been observed.

In all cases of initiation and resumption (after a break of 4 hours or more) of the therapy cycle, monitoring by a healthcare professional or hospitalization of the patient is recommended.

Infusion packets of Blincito must be prepared for infusion within 24 hours, 48 hours, 72 hours or 96 hours. See section “Method of administration”.

Dosing regimen

Recurrent or refractory Vlymphocyte precursor OLL

A patient with relapsed or refractory Vlymphocyte Precursor OLL may receive 2 cycles of therapy. The therapy cycle lasts 28 days (4 weeks); the drug is administered by prolonged intravenous infusion. After each cycle of therapy a 14-day (2 weeks) break follows.

Patients who have achieved complete remission (PR/PRG*) after two cycles of therapy may receive up to 3 additional consolidating cycles of Blincito according to the results of individual benefit-risk assessment.

The recommended daily dose of drug is determined by the patient’s body weight (see table 1). Patients with a body weight ≥ 45 kg should receive the drug in a fixed dose; in patients with a body weight less than 45 kg, the dose is calculated according to body surface area (BSA).

Table 1. Recommended doses of Blincito for patients with relapsed or refractory Vlymphocyte Precursor LLL

Patient weight

Following cycles

Days 1-7

Days 8-28

Days 29-42

Days 1-28

Days 29-42

./td>

45 kg or more

(fixed dose)

9 mcg/day (by prolonged infusion)

28 mcg/day (by prolonged infusion)

14-day
break

28 mcg/day (by prolonged infusion)

14-day
break

Less than 45 kg

(dose calculated based on PPT)

5 µg/m2/day by prolonged infusion

(but no more than 9 mcg/day)

15 mcg/m2
day (by prolonged infusion)

(but no more than 28 mcg/day)

15 mcg/m2 per day (by prolonged infusion)

/p>

(but no more than 28 mcg/day)

First recurrence of ALL from high-risk Vlymphocyte precursors

Children with a first recurrence of ALL from high-risk Vlymphocyte precursors may receive 1 cycle of therapy with Blincito after induction therapy and 2 blocks of consolidation chemotherapy. The duration of one cycle of therapy is 28 days (4 weeks); the drug is administered by prolonged infusion. The recommended daily doses, depending on the body weight of the child, are shown in Table 2.

Table 2. Recommended doses of Blincito for postinduction chemotherapy in children with first relapse of high risk Vlymphocyte precursors

One consolidation cycle

Patients with a body weight of 45 kg or more

(fixed dose)

Patients weighing less than 45 kg

(dose calculated based on PPT)

Days 1-28

28 mcg/day

15 mcg/m2/day

(but no more than 28 µg/day)

In adult patients, an intravenous dose of dexamethasone of 20 mg is required 1 hour before the start of each cycle of Blintzito therapy.

In children, a dose of 10 mg/m2 (but no more than 20 mg) of dexamethasone should be given orally or intravenously 6-12 hours before the start of Blincito infusion (on day 1 of the first cycle of therapy). Dexamethasone at a dose of 5 mg/m2 is then administered orally or intravenously 30 minutes before the start of the Blincito infusion (on day 1 of the 1st cycle).

To reduce body temperature during the first 48 hours of each cycle of therapy, antipyretics (such as paracetamol) are recommended.

Before and during the course of therapy with Blincito, intrathecal prophylactic administration of chemotherapeutic agents is recommended to prevent central nervous system recurrence of OLV.

Pre-phase therapy in patients with a large tumor mass

Patients with ≥50% leukemic blasts in bone marrow or > 15,000 leukemic blasts in 1 µL of peripheral blood should receive dexamethasone (at a dose no higher than 24 mg/day).

VLD from Vlymphocyte precursors with the presence of MOB

.When considering the use of Blincito for therapy of MOB-positive ALL from Vlymphocyte precursors without the Philadelphia chromosome, MOB quantification results must be confirmed by a validated assay with a minimum sensitivity of 10-4. Clinical analysis of MOB, regardless of the choice of methodology, must be performed in a qualified laboratory using a technique that meets generally accepted technical requirements.

Patients may receive 1 cycle of induction therapy followed by up to 3 additional cycles of consolidation therapy with Blincito. One cycle of induction or consolidation therapy with Blincito lasts 28 days (4 weeks), during which time there is a continuous intravenous infusion of the drug, followed by a 14-day (2 week) pause (total duration: 42 days). The majority of patients who had a response to blinatumomab achieved this response after 1 cycle. Therefore, the potential benefit and risks associated with continued therapy in patients who do not demonstrate hematologic and/or clinical improvement after 1 cycle of therapy should be evaluated by the treating physician.

Recommended doses for patients with a body weight of at least 45 kg:

Cycles of Therapy

Interaction

Special Instructions

Traceability

To improve traceability of biologic drugs, the name and series number of the drug used must be accurately documented.

Neurological disorders

There have been cases of neurological disorders, including death, during the use of the drug. Grade 3 or higher neurologic abnormalities (according to the Common Terminology Criteria for Adverse Events Version 4.0) (i.e. severe or life-threatening) that occurred after initiation of blinatumomab therapy were encephalopathy, seizures, seizure disorders, speech disorders, mental confusion, disorientation, and movement and balance coordination disorders. In patients who experienced neurologic abnormalities, the median time to their first episode was in the range of the first 2 weeks of therapy; most of these resolved after temporary discontinuation of therapy, and they infrequently led to early withdrawal of Blincito.

Elderly patients may be more prone to develop serious neurological abnormalities, particularly cognitive impairment, encephalopathy, and confusion.

Patients with a history of neurological disorders (in particular dizziness, hypoesthesia, hyporeflexia, tremor, dysesthesia, paresthesia and memory disturbances) were characterized by a higher frequency of neurological disorders (in particular tremor, dizziness, confusion, encephalopathy and ataxia) on therapy. In these patients, the median time to the development of the first neurological disorder corresponded to the first cycle of therapy.

The experience of using the drug in patients with a history or currently clinically significant CNS pathology (in particular epilepsy, seizures, paresis, aphasia, stroke, severe brain damage, dementia, Parkinson’s disease, cerebellar pathology, syndrome of organic brain damage and psychosis) is limited because they were excluded from clinical trials. There is a possibility of increased risk of neurological impairment in this patient population. The potential benefit of therapy must be carefully weighed against the risk of neurologic impairment and special care must be taken when using Blincito in these patients.

The experience with blincitumomab in patients with documented CNS or cerebrospinal fluid (CSF) lesions in ALL is limited. However, in clinical trials, patients received blinatumomab after the elimination of blasts from the CSF as a result of CNS-directed therapy (e.g., intrathecal chemotherapy). Therefore, after elimination of blasts from the CSF, it is possible to start therapy with blincitumab.

A neurological examination prior to initiation of therapy with Blincito and clinical monitoring of patients for signs and symptoms of neurological abnormalities (e.g., by a handwriting test) is recommended. To correct these signs and symptoms until resolution, temporary or complete withdrawal of therapy with Blincito may be required (see section “Dosage and administration”). If seizures develop, secondary prophylaxis with an appropriate anticonvulsant (e.g., levetiracetam) is recommended.

Infections

In patients receiving blinatumomab, serious infections have been reported, including sepsis, pneumonia, bacteremia, opportunistic infections, and infections at the catheter site, some of which were life threatening or fatal. Adult patients who had an Eastern United States Cooperative Oncology Group (ECOG) general status index at baseline of 2 had an increased incidence of serious infections compared with patients who had an ECOG general status index of < 2. There is limited experience with Blincito in patients with active uncontrolled infections.

Patients receiving Blincito should be clinically monitored for signs and symptoms of infections and treated appropriately. Correction of infections may require temporary or complete discontinuation of therapy with Blincito (see “Dosage and administration”).

Cytokine Release Syndrome and Infusion Reactions

In patients treated with Blincito, there have been cases of life-threatening or fatal (≥ grade 4) cytokine release syndrome (CRS) (see “Side Effects”).

Serious adverse events that may have been signs or symptoms of SVC were pyrexia, asthenia, headache, hypotension, elevated total bilirubin, and nausea; infrequently, these adverse events led to early withdrawal of therapy with Blincito. The median time to development of SVC was 2 days. Patients should be closely monitored for signs and symptoms of these adverse events.

Disseminated intravascular coagulation syndrome (DIC) and increased capillary permeability syndrome (CAPS) (e.g., hypotension, hypoalbuminemia, edema, and hemoconcentration) are frequently seen with VIC (see section “Adverse effects”). Patients who develop PPS should receive appropriate treatment.

Hemophagocytic syndrome/macrophage activation syndrome has been infrequently reported in HIC.

Infusion reactions may be clinically indistinguishable from manifestations of HIC (see section “Adverse effects”). Infusion reactions usually develop rapidly (within 48 hours after the start of the infusion). However, a number of patients have had delayed infusion reactions or developed them during subsequent cycles of therapy. Patients should be closely monitored for infusion reactions, especially at the beginning of the first and second cycles of therapy, and receive appropriate treatment. In order to reduce the severity of pyrexia during the first 48 hours of each cycle of therapy, the use of antipyretics (e.g., paracetamol) is recommended. In order to reduce the risk of SVC, it is important to start therapy with Blincito (on days 17 of therapy cycle 1) at the recommended starting dose (see section “Dosage and administration”).

The correction of these reactions may require temporary or complete discontinuation of Blincito therapy (see “Dosage and administration”).

Tumor Lysis Syndrome (TLS)

Tumor Lysis Cases, including life-threatening or fatal (≥4 grade), have been reported in patients treated with Blincito.

In therapy with Blincito, appropriate preventive measures, including aggressive hydration and antihyperuricemic therapy (such as allopurinol or rasburicase) to prevent and correct SLOs, especially in patients with significant leukocytosis or a significant tumor mass, are necessary. Patients should be closely monitored for signs and symptoms of SLOs, including monitoring renal function and water balance during the first 48 hours after the first infusion of the drug. In clinical trials, an increased incidence of SLOs has been observed in patients with moderate renal dysfunction compared to patients with normal or mild renal dysfunction. Correction of these reactions may require temporary or complete discontinuation of therapy with Blincito (see section “Dosage and administration”).

Neutropenia and febrile neutropenia

In patients treated with Blincito there were cases of neutropenia and febrile neutropenia, including life-threatening ones. Monitoring of laboratory parameters (including, but not limited to: leukocyte count and absolute neutrophil count) during the infusion of Blincito, especially during the first 9 days of the first cycle of therapy, and adequate correction of these reactions is necessary.

Elevations in hepatic enzyme activity

Blincito therapy has been associated with transient elevations in hepatic enzyme activity. Most of these cases were observed during the first week of therapy and did not require temporary discontinuation or complete withdrawal of Blincito (see section “Side effects”).

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transpeptidase (GGTP) and total bilirubin concentration in blood should be monitored before and during the therapy with Blincito, especially during first 48 h of the first two cycles of therapy. Correction of these reactions may require temporary or complete discontinuation of therapy with Blincito (see section “Dosage and administration”).

Pancreatitis

Incidents of pancreatitis, including life-threatening or fatal, have been reported in patients treated with Blincito in clinical trials and during its use during the period after the drug registration. High-dose steroid therapy may, in some cases, contribute to the development of pancreatitis.

Patients should be closely monitored for symptoms and signs of pancreatitis through objective examination, serum laboratory tests (amylase and lipase) and abdominal examinations (e.g., ultrasound) and other adequate diagnostic tests. Correction of pancreatitis may require temporary or complete discontinuation of therapy with Blincito (see section “Dosage and administration”).

Leukoencephalopathy, including progressive multifocal leukoencephalopathy

. Cases of leukoencephalopathy on magnetic resonance imaging (MRI) of the brain have been reported in patients treated with Blincito, especially those previously treated with cranial radiation therapy and anti-leukemic chemotherapy (including high-dose systemic methotrexate therapy or intrathecal cytarabine therapy). The clinical significance of these changes recorded in radiation studies is unknown.

Because of the potential risk of progressive multifocal leukoencephalopathy (PML), patients should be monitored for relevant signs and symptoms. If its development is suspected, a consultation with a neurologist, MRI of the brain and examination of cerebrospinal fluid (CSF) should be considered – see section “Side effects”.

Recurrence of CD19-negative ALL

There have been cases of CD19-negative ALL from Vlymphocyte precursors in relapsed patients treated with Blincito. Special attention should be paid to the evaluation of CD19 expression in bone marrow studies.

Transformation of OLL into acute myeloid leukemia (AML)

Transformation of OLL into AML has rarely been seen in relapsed patients treated with Blincito, including patients without immunophenotypic and/or cytogenetic abnormalities in the primary diagnosis. All relapsed patients should be monitored for the presence of OML.

Immunization

The safety of immunization with live viral vaccines during or after completion of Blincito therapy has not been studied. Therefore, immunization with live viral vaccines is not recommended for at least 2 weeks before starting therapy with Blincito, during the course of therapy with it, and until the Blymphocyte count has returned to normal levels after the last cycle of therapy.

Due to potential Vlymphocyte depletion in newborns after administration of blinatumomab during pregnancy, newborns should be monitored for Vlymphocyte depletion and immunizations with live viral vaccines should be delayed until the child’s Vlymphocyte count has recovered (see “Administration during pregnancy and breastfeeding”).

Contraception

Women of childbearing potential must use effective contraception during Blincito therapy and for at least 48 hours thereafter (see “Use in pregnancy and breastfeeding”).

Mistakes in the use of the drug

There have been cases of errors in the use of Blincito. It is extremely important to follow the instructions for preparation (including reconstitution and dilution) and administration of the drug to minimize these errors (including underdose and overdose of the drug) (see “How to Use and Dose”).

Associates with known effects

The drug Blincito contains less than 1 mmol (23 mg) of sodium in volume administered over 24 hours, which means it can be considered virtually sodium-free.

Influence of the medicinal product for medical use on driving and operating machinery

Blincito had a significant effect on driving and operating machinery. Confusion and disorientation, impaired coordination of movements and balance, as well as increased risk of seizures and impaired consciousness may occur (see section “Cautions”). Due to the potential risk of neurological disorders, patients receiving blinatumomab should refrain from driving, engaging in dangerous work or other activities, in particular, driving vehicles or working with heavy or potentially dangerous mechanisms, during the therapy with this drug. Patients should be instructed about the possibility of developing neurological disorders.

Synopsis

White or light yellow powder or amorphous mass.

Reconstituted drug: A colorless to light yellow liquid, transparent or slightly opalescent, free from mechanical inclusions.

Stabilizer solution for preparation of solution for infusion:colorless to light yellow liquid, clear or slightly opalescent, free from mechanical inclusions.

Contraindications

Side effects

Safety Profile Overview

The adverse events described in this section have been identified in clinical trials in patients with Vlymphocyte Precursor Leukemia (N = 1045).

The most serious adverse reactions that may develop during therapy with blinatumomab are: infections (22.6%), neurologic disorders (12.2%), neutropenia/febrile neutropenia (9.1%), cytokine release syndrome (2.7%) and tumor lysis syndrome (0.8%).

The most common adverse reactions were: Pyrexia (70.8%), infections due to an unspecified pathogen (41.4%), infusion reactions (33.4%), headache (32.7%), nausea (23.9%), anemia (23.3%), thrombocytopenia (21.6%), edema (21.4%), neutropenia (20.8%), febrile neutropenia (20.4%), diarrhea (19.7%), vomiting (19.0%), skin rash (18.0%), increased liver enzyme activity (17.2%), cough (15.0%) bacterial infections (14.1%), tremor (14.1%), cytokine release syndrome (13.8%), leukopenia (13.8%), constipation (13.5%), reduced immunoglobulin concentration (13.4%) viral infections (13.3%), hypotension (13.0%), back pain (12.5%), chills (11.7%), abdominal pain (10.6%), tachycardia (10.6%), insomnia (10.4%), limb pain (10.1%) and fungal infections (9.6%).

Table listing of adverse reactions

The adverse reactions listed below are grouped into organ system classes and frequency categories. The incidence categories were determined based on the baseline incidence of each adverse reaction in clinical trials in patients with Vlymphocyte precursor OHL (N = 1045). Within each organ system class, adverse reactions are presented in descending order of severity.

MedDRA organ systems class.

very often

(≥1/10)

Pneumonia

Fungal infectionsa, b

Blood and lymphatic system disorders

/p>

Febrile neutropenia

Anemia1

Neutropenia2

Thrombocytopenia3

Leukopenia4

Leukocytosis5

Lymphopenia6

Lymphadenopathy

Hematophagocytic syndrome

Immune system disorders

Cytokine release syndromea

Hypersensitivity

Cytokine crisis

Eating and metabolic disorders

Tumor lysis syndrome

Mental disordersa

Insomnia

Confusion

Disorientation

Nervous system disordersa

Headache

Tremors

Encephalopathy

Aphasia

Paresthesia

Seizure disorder

Cognitive disorder

Memory impairment

Dizziness

Drowsiness

Hypesthesia

Cranial nerve impairmentb

Ataxia

/td>

Speech impairment

Cardiac disorders

Tachycardia7

Vascular system disorders

Hypotension

sup>8

Hypertension9

Hyperemia

capillary permeability syndrome

Respiratory, thoracic, and mediastinal disorders

/p>

Cough

Dyspnea

Productive cough

Respiratory failure

Wheezing

Dyspnea on physical activity

Acute respiratory failure

Digestive system disorders

Nausea

Diarrhea

Vomiting

Constipation

Pain in the stomach

/p>

Pancreatitisa

Hepatobiliary system disorders

Hyperbilirubinemiaa,10

Skin and subcutaneous tissue disorders

Rash11

Disorders of the musculoskeletal system and connective tissue

Back pain

Limb pain

Bone pain

/p>

Systemic disorders and complications at the injection site

/p>

Pyrexia12

Chills

Edema13

Chest pain14

Pain

Changes in the results of laboratory and instrumental tests

Changes in laboratory and instrumental results/p>

Increased activity of liver enzymesa, 15

Decreased concentration of immunoglobulins16

An increase in body weight

Increased blood alkaline phosphatase activity

Injuries, poisonings, and complications of procedures

Infusion reaction17

a For more information, see “Description of individual adverse reactions”.

b Group MedDRA high-level terms (MedDRA version 23.0).

The adverse event terms corresponding to identical pathological conditions were grouped as one adverse reaction in the table above. The terms were grouped as follows.

1 Anemia included anemia and decreased hemoglobin concentration.

2 Neutropenia included neutropenia and decreased neutrophil count.

3 Thrombocytopenia included decreased platelet count and thrombocytopenia.

4 Leukopenia included leukopenia and decreased white blood cell count.

5 Leukocytosis included leukocytosis and increased leukocyte count.

6 Lymphopenia included decreased lymphocyte count and lymphopenia.

7 Tachycardia included sinus tachycardia, supraventricular tachycardia, tachycardia, atrial tachycardia, and ventricular tachycardia.

8 Hypotension included decreased blood pressure and hypotension.

9 Hypertension included increased blood pressure and hypertension.

10 Hyperbilirubinemia included increased blood bilirubin concentration and hyperbilirubinemia.

11 .Skin rashes included erythema, skin rashes, erythematous skin rashes, generalized skin rashes, macular skin rashes, maculopapular skin rashes, itchy skin rashes, catheter site skin rashes, pustular skin rashes, genital skin rashes, papular skin rashes and vesicular skin rashes.

12 Pyrexia included elevated body temperature and pyrexia.

13 .Edema included bone marrow edema, periorbital edema, eyelid edema, eye edema, lip edema, facial edema, local edema, generalized edema, edema, peripheral edema, infusion site edema, renal edema, scrotal edema, genital edema, lung edema, laryngeal edema, angioedema, peroral edema and lymphoedema.

14 Chest pain included chest discomfort, chest pain, musculoskeletal chest pain, and noncardiac chest pain.

15 Increased liver enzyme activity included increased alanine aminotransferase activity, increased aspartate aminotransferase activity, increased gamma-glutamyl transpeptidase activity, increased hepatic enzyme activity, increased liver function test score, and increased transaminase activity.

16 Decreased immunoglobulin concentrations included decreased immunoglobulin G blood concentration, decreased immunoglobulin A blood concentration, decreased immunoglobulin M blood concentration, decreased globulin concentration, hypogammaglobulinemia, hypoglobulinemia and reduced immunoglobulin concentration.

17 Infusion reactions was a composite term that included an infusion reaction and the following adverse events noted within the first 48 hours of infusion and lasting for ≤2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, skin rash, tachypnea, facial edema, facial swelling, and erythematous skin rash.

Description of individual adverse reactions

Neurologic disorders

. In a randomized phase III clinical trial (N = 267) and a noncomparative phase II clinical trial (N = 189) involving patients with Philadelphia chromosome negative relapsed or refractory Vlymphocyte precursor OLL treated with Blincito, 66.0% of patients experienced one or more neurologic adverse reactions (including psychiatric disorders), primarily CNS involvement. Serious and ≥3 severity neurologic adverse reactions were reported in 11.6% and 12.1% of patients, respectively; of these, encephalopathy, tremor, aphasia, and confusion were the most common serious adverse events. Most of the neurological disorders (80.5%) were clinically reversible and resolved after suspension of therapy with Blincito. The median time to the development of the first adverse event was within the first two weeks of therapy. There was one case of fatal encephalopathy in a noncomparative phase II study conducted early in the clinical research program.

Neurological adverse events occurred in 62.2% of adult patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL (N = 45). Serious neurologic adverse events and grade 3 or higher neurologic adverse events were reported in each of these categories in 13.3% of adult patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL.

Neurologic adverse events occurred in 71.5% of adult patients with MOB-positive Vlymphocyte precursor OLL (N = 137); 22.6% of patients had serious adverse events. Grade 3 and grade 4 adverse events occurred in 16.1% and 2.2% of adult patients with MOB-positive Vlymphocyte precursor OLL, respectively.

Principles of clinical management of neurologic disorders are described in the “Special Indications” section.

Infections

Life-threatening or fatal (≥4 grade) viral, bacterial, and fungal infections have been reported in patients treated with Blincito. Additionally, in a phase II clinical trial in adult patients with relapsed or refractory Philadelphia chromosome-negative Vlymphocyte precursor OLL, cases of reactivation of viral infections (e.g., polyoma (BK)) were reported. Patients with relapsed or refractory Philadelphia chromosome-negative Vlymphocyte precursor OLL who had an ECOG general status index = 2 at baseline had increased rates of serious infections compared to patients who had an ECOG general status index of < 2. For principles of clinical management of infection, see “Special Instructions”.

Cytokine Release Syndrome (CRS)

. In a randomized phase III clinical trial (N = 267) as well as a noncomparative phase II clinical trial (N = 189) involving patients with Philadelphia chromosome negative relapsed or refractory Vlymphocyte precursor OLL treated with Blincito, SVC was reported in 14.7% of patients. Serious SVC occurred in 2.4% of patients; the median time to development was 2 days.

Cytokine release syndrome occurred in 8.9% of adult patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL (N = 45); 2.2% of patients had serious adverse events. No grade ≥3 or ≥4 adverse events were reported.

Cytokine release syndrome was reported in 2.9% of adult patients with MOB-positive Vlymphocyte precursor OLL (N = 137). Grade 3 adverse events and serious adverse events occurred in 1.5% and 1.5% of adult patients with MOB-positive Vlymphocyte precursor OLL, respectively; no adverse events ≥ grade 4 were noted.

The syndrome of increased capillary permeability was reported in one patient in a phase II clinical trial involving adult patients with Philadelphia chromosome negative relapsed or refractory Vlymphocyte precursor OLL and in one patient in a phase II clinical trial involving adult patients with MOB-positive Vlymphocyte precursor OLL. Syndrome of increased capillary permeability was not observed in adult patients in a phase II clinical trial involving patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL.

Principles of clinical management of SVC are described in the Special Instructions section.

Elevation of hepatic enzyme activity

. In a randomized phase III clinical trial (N = 267) and a noncomparative phase II clinical trial (N = 189) involving patients with Philadelphia chromosome negative relapsed or refractory Vlymphocyte precursor OLL treated with Blincito, 22.4% of patients experienced increased liver enzyme activity and associated signs or symptoms. Serious adverse reactions and adverse reactions of ≥3 grade (in particular, increased ALT activity, increased AST activity, and increased bilirubin concentration in the blood) were noted in 1.5% and 13.6% of patients, respectively. Median time to development of the first episode of these adverse reactions was 4 days from the start of therapy with Blincito.

Elevated hepatic enzyme activity was noted in 17.8% of adult patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL (N = 45); 2.2% of patients had serious adverse events. Grade ≥3 and ≥4 adverse events occurred in 13.3% and 6.7% of adult patients with Philadelphia chromosome-positive relapsed or refractory Vlymphocyte precursor OLL, respectively.

Elevated liver enzyme activity was noted in 12.4% of adult patients with MOB-positive Vlymphocyte precursor OLL (N = 137). Grade 3 and grade 4 adverse events ≥3 and ≥4, respectively, were noted in 8.0% and 4.4% of adult patients with MOB-positive Vlymphocyte precursor OLL.

The duration of adverse liver reactions was usually short and resolved rapidly, often without discontinuation of Blincito therapy.

Principles of clinical management of cases of increased hepatic enzyme activity are described in the section “Special Indications”.

Pancreatitis

Cases of pancreatitis (life-threatening or fatal) have been reported in patients treated with Blincito in clinical trials and in post-registration use. The median time to development of these adverse reactions was 7.5 days. Principles of clinical management of pancreatitis are described in the section “Special Indications”.

Leukoencephalopathy, including progressive multifocal leukoencephalopathy

Cases of leukoencephalopathy have been observed. Serious adverse events, including confusion, tremor, cognitive impairment, encephalopathy and seizures, have been reported in patients in whom MRI/CT of the brain revealed changes consistent with leukoencephalopathy. Although there is a possibility of progressive multifocal leukoencephalopathy (PML), no confirmed cases of PML have been reported in clinical trials to date.

Children

. The drug Blincito was studied in children with relapsed or refractory Vlymphocyte precursor-derived OLL in a noncomparative phase I/II study of the drug with escalation followed by dose-matching evaluation (MT103-205), which included 70 children aged 7 months to 17 years who received the drug in the recommended dosing regimen.

The most frequently reported serious adverse events were: pyrexia (11.4%), febrile neutropenia (11.4%), cytokine release syndrome (5.7%), sepsis (4.3%), device-related infection (4.3%), overdose (4.3%), seizures (2.9%), respiratory failure (2.9%), hypoxia (2.9%), pneumonia (2.9%), and multiple organ failure (2.9%).

The adverse reactions reported in children treated with Blincito were similar in type to those reported in adult patients. The undesirable reactions noted more frequently (the difference was ≥10%) in children compared to adults were: anemia, thrombocytopenia, leukopenia, pyrexia, infusion reactions, weight gain, and arterial hypertension.

The types and frequency of adverse events were similar in children of different subgroups (allocated according to sex, age, and geographic region).

The MT103-205 study reported a case of fatal heart failure with life-threatening cytokine release syndrome (CRS) and tumor lysis syndrome (TLS) when using the drug at a dose higher than recommended; see section “Special Precautions”.

The use of Blincito was also evaluated in children with first relapsed high risk Vlymphocyte precursor OLL in a randomized controlled, open-label phase III study (20120215) in which 54 patients aged 1 to 18 years received the drug at the recommended dose for treatment of first relapsed high risk Vlymphocyte precursor OLL. The safety profile of Blincito in study 20120215 was consistent with the safety profile in the study population of children with relapsed or refractory Vlymphocyte precursor OLL.

Other special populations

The experience with Blincito in elderly patients (≥75 years) is limited. In general, the safety profile in elderly patients (≥65 years) and patients younger than 65 years receiving Blincito was comparable. However, elderly patients may be more susceptible to serious neurological events such as cognitive impairment, encephalopathy and confusion.

Elderly patients with MOB-positive OLL receiving Blincito may have an increased risk of hypogammaglobulinemia compared to younger patients. It is recommended to monitor immunoglobulin concentrations in elderly patients during therapy with Blincito.

The safety of Blincito in patients with severe renal impairment has not been evaluated.

Immunogenicity

In clinical studies in adult patients treated with Blincitso, only 3% of patients tested had antibodies to blinatumomab. Antibodies to blinatumomab with neutralizing activity in vitro were detected in six of these patients. No antibodies to blinatumomab were found in clinical studies involving children treated with blinatumomab in relapsed or refractory ALS.

If antibody production to blinatumomab with a clinically significant effect is suspected, the consumer claims organization in the Russian Federation should be contacted to discuss antibody testing.

Pregnancy use

Pregnancy

There have been no studies of reproductive toxicity of blinatumomab. No evidence of embryotoxicity or teratogenicity was found in an embryofetal toxicity study performed in mice using a murine surrogate molecule. In pregnant mice, the expected depletion of B- and T-cells was observed, but hematological effects on the fetus were not evaluated.

There are no data on the use of blinatumomab in pregnant women.

Blinatumomab should not be used during pregnancy unless the potential benefit to the mother outweighs the possible risk to the fetus.

Women of childbearing potential should use effective contraception during therapy with blinatumomab and for at least 48 hours thereafter (see “Special Precautions”).

When the drug is used during pregnancy, B-cell depletion due to its pharmacological properties may occur in neonates. Therefore, neonates should be monitored for V-cell depletion and vaccination with live viral vaccines should be delayed until the child’s V-cell count has recovered (see “Special Precautions”).

Breastfeeding period

. It has not been determined whether blinatumomab penetrates into breast milk, but given the potential for adverse effects in infants, breastfeeding is contraindicated during and for at least 48 hours after administration of Blincito.

Fertility

There have been no studies to evaluate the effects of Blincito on fertility. No effects on the reproductive organs of male or female mice were found in a 13-week toxicity study with a mouse surrogate molecule.