Blincyto^® (Powder) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

Or

Amgen Technology (Ireland), Unlimited Company (Ireland)

Labeled By

AMGEN EUROPE, B.V. (Netherlands)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

Quality Control Release

AMGEN EUROPE, B.V. (Netherlands)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

ATC Code

L01FX07 (Blinatumomab)

Active Substance

Blinatumomab (Rec.INN registered by WHO)

Dosage Form

Blincyto®

Powder for concentrate for solution for infusion 35 mcg: fl. 1 pc. in a set with stabilizer solution

Dosage Form, Packaging, and Composition

Powder for concentrate for solution for infusion in the form of a powder or amorphous mass of white or light yellow color; reconstituted medicinal product: a colorless to light yellow liquid, clear or slightly opalescent, free from mechanical inclusions; stabilizer solution for preparation of solution for infusion: a colorless to light yellow liquid, clear or slightly opalescent, free from mechanical inclusions.

* nominal volume of blinatumomab; an excess amount of 38.5 mcg is taken to extract 35 mcg of blinatumomab.

Excipients: citric acid monohydrate – 3.68 mg, trehalose dihydrate – 105 mg, lysine hydrochloride – 25.55 mg, polysorbate 80 – 0.7 mg, sodium hydroxide – q.s. to pH 7.0.

Stabilizer solution for preparation of solution for infusion (1 fl.) citric acid monohydrate – 52.5 mg, lysine hydrochloride – 2283.8 mg, polysorbate 80 – 10 mg, sodium hydroxide – q.s. to pH 7.0, water for injections – q.s. to 10 ml.

Glass vials with a volume of 4 ml (1) in a set with stabilizer solution (fl. 10 ml 1 pc.) – blister packs (1) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents; monoclonal antibodies and their drug conjugates; other monoclonal antibodies and their drug conjugates

Pharmacological Action

Antitumor agent, bispecific T-cell engager. It is a molecule 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. Blinatumomab activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The antitumor activity of blinatumomab is independent of the presence of T-lymphocytes with specific TCRs and peptide antigens on the surface of tumor cells, is polyclonal in nature and independent of the type of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab-mediated formation of a cytolytic synapse between a T-cell and a tumor cell leads to the release of proteolytic enzymes that destroy target cells, both in the proliferation stage and in the resting stage. Blinatumomab transiently activates increased expression of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines and proliferation of T-cells, and leads to the elimination of CD19+ cells.

Stable immune pharmacodynamic responses were observed in patients in 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.

Pharmacokinetics

The pharmacokinetics of blinatumomab in adult patients is linear in the dose range from 5 to 90 mcg/m²/day (approximately equivalent to from 9 to 162 mcg/day). After continuous IV infusion, C_ss in serum is reached within a day and remains stable over time. The increase in mean C_ss values is 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 relapsed/refractory acute lymphoblastic leukemia, the mean (SD) C_ss was 228 (356) pg/ml and 616 (537) pg/ml, respectively.

The estimated mean (SD) volume of distribution in the terminal phase (V_z) during continuous IV infusion of blinatumomab is 4.52 (2.89) L.

The estimated mean (SD) systemic clearance during continuous IV infusion in patients receiving Blinatumomab in clinical studies was 2.92 (2.83) L/h. The mean (SD) T_1/2 is 2.11 (1.42) h. At the studied clinical doses, an insignificant amount of blinatumomab was excreted from the body in the urine.

Indications

As monotherapy for the treatment of CD19-positive relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL) in adults. Patients with Philadelphia chromosome-positive precursor B-cell ALL must be resistant to therapy with at least two tyrosine kinase inhibitors (TKIs) and have no alternative treatment options.

As monotherapy for the treatment of CD19-positive, Philadelphia chromosome-negative precursor B-cell ALL in adults in the first or second complete remission phase with minimal residual disease (MRD) >0.1%.

As monotherapy for the treatment of CD19-positive, Philadelphia chromosome-negative relapsed or refractory precursor B-cell ALL (after at least two lines of prior therapy or after allogeneic hematopoietic stem cell transplantation) in children aged 1 year or older.

As monotherapy for the treatment of children aged 1 year and older with first relapse of high-risk CD19-positive, Philadelphia chromosome-negative precursor B-cell ALL as part of consolidation therapy.

ICD codes

Dosage Regimen

It is administered as a continuous IV infusion using an IV infusion system.

The dose and treatment regimen are established individually, depending on the indications and the patient’s age.

Premedication is performed 1 hour before the start of each treatment cycle.

The use of an antipyretic is recommended to reduce pyrexia during the first 48 hours of each treatment cycle.

In case of adverse reactions, dose adjustment is necessary, which is carried out according to a special scheme.

Intrathecal prophylactic chemotherapy is recommended before and during blinatumomab therapy to prevent CNS relapse of ALL.

Adverse Reactions

Infections and infestations very common – bacterial infections, fungal infections, viral infections, infections with other pathogens; common – sepsis, pneumonia.

Blood and lymphatic system disorders very common – febrile neutropenia, anemia, neutropenia, thrombocytopenia, leukopenia; rare – hemophagocytic histiocytosis.

Immune system disorders very common – cytokine release syndrome; common – cytokine storm, hypersensitivity, decreased immunoglobulins.

Metabolism and nutrition disorders very common – hypokalemia, hypomagnesemia, hyperglycemia, decreased appetite; common – hypophosphatemia, hypoalbuminemia, weight increased, tumor lysis syndrome. More frequent in children – hypophosphatemia, hypocalcemia, increased blood LDH.

Nervous system disorders very common – headache, tremor, dizziness; common – encephalopathy, aphasia, paresthesia, seizures, cognitive disorder, speech disorders, memory impairment.

Psychiatric disorders very common – insomnia; common – confusion, disorientation.

Cardiac disorders very common – decreased blood pressure; common – tachycardia; rare – capillary leak syndrome. More frequent in children – arterial hypertension.

Respiratory, thoracic and mediastinal disorders very common – cough. More frequent in children – rhinitis, epistaxis.

Gastrointestinal disorders very common – nausea, constipation, diarrhea, abdominal pain, vomiting, increased ALT, increased AST; common – increased blood bilirubin, increased GGT.

Skin and subcutaneous tissue disorders very common – rash.

Musculoskeletal and connective tissue disorders very common – back pain, pain in extremity, arthralgia, bone pain.

General disorders and administration site conditions very common – hyperthermia, peripheral edema, chills, fatigue, chest pain.

Other very common – infusion reactions (and associated symptoms, including wheezing, flushing, facial edema, dyspnea, decreased blood pressure and increased blood pressure).

Contraindications

Hypersensitivity to blinatumomab, severe renal failure, severe hepatic failure, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use effective methods of contraception during the course of blinatumomab therapy and for at least 48 hours thereafter.

Use in Hepatic Impairment

According to the results of pharmacokinetic analysis, baseline liver function did not affect the exposure value of blinatumomab, and therefore adjustment of the initial dose of the drug in this situation is not required. Safety and efficacy in patients with severe hepatic impairment have not been studied.

Use in Renal Impairment

According to the results of pharmacokinetic analysis, no dose adjustment is required in patients with mild or moderate renal impairment. The safety and efficacy of Blincyto^® in patients with severe renal impairment have not been studied.

Pediatric Use

The safety and efficacy of blinatumomab in children under 1 year of age have not been established. There are no data on use in children under 7 months of age.

Geriatric Use

No dose adjustment is required in elderly patients (> 65 years). Experience of use in patients over 75 years of age is limited.

Special Precautions

A higher frequency of nervous system adverse reactions (in particular, tremor, dizziness, confusion, encephalopathy and ataxia) was observed during therapy in patients with a history of neurological disorders (including dizziness, paresthesia, hyporeflexia, tremor, memory impairment).

The potential benefit of therapy must be carefully weighed against the risk of neurological disorders and Blinatumomab should be used with particular caution in these patients. Elderly patients may be more prone to developing serious neurological disorders.

Neurological examination prior to initiation of blinatumomab therapy and clinical monitoring of patients for signs and symptoms of neurological disorders is recommended. Temporary or complete discontinuation of blinatumomab therapy may be required to manage these signs and symptoms until resolution. If seizures develop, secondary prophylaxis with an appropriate anticonvulsant is recommended.

Experience in patients with active uncontrolled infections is limited. Patients receiving Blinatumomab require clinical monitoring for the appearance of symptoms of infections and appropriate treatment. Management of infections may require temporary or complete discontinuation of blinatumomab therapy.

Infusion reactions may be clinically indistinguishable from manifestations of cytokine release syndrome. Patients require careful clinical monitoring for the development of infusion reactions, especially at the beginning of the first and second treatment cycles, and receive appropriate treatment.

During blinatumomab therapy, appropriate prophylactic measures are necessary, including aggressive hydration and antihyperuricemic therapy (e.g., with allopurinol) to prevent and manage tumor lysis syndrome, especially in patients with marked leukocytosis or significant tumor mass. Patients should be closely monitored for signs and symptoms of tumor lysis syndrome, including monitoring of renal function and fluid balance during the first 48 hours after the first infusion. In clinical studies, patients with moderate renal impairment had an increased incidence of tumor lysis syndrome compared to patients with normal renal function or mild impairment. Management of these reactions may require temporary or complete discontinuation of blinatumomab therapy.

Monitoring of laboratory parameters (including white blood cell count and absolute neutrophil count) during blinatumomab infusion is necessary, especially during the first 9 days of the first treatment cycle, as well as adequate management of these reactions.

Monitoring of liver function parameters is necessary during treatment.

Patients should be closely monitored for symptoms and signs of pancreatitis through physical examination, serum laboratory tests (amylase and lipase) and abdominal imaging (e.g., ultrasound) and other appropriate diagnostic tests. Management of pancreatitis may require temporary or complete discontinuation of blinatumomab therapy.

Due to the potential risk of progressive multifocal leukoencephalopathy, patients should be monitored for relevant signs and symptoms. If it is suspected, consultation with a neurologist, brain MRI and examination of cerebrospinal fluid should be considered.

When performing a bone marrow examination, special attention should be paid to the assessment of CD19 expression.

Transformation of ALL to AML has been rarely reported in patients with relapse receiving Blinatumomab, including in patients without immunophenotypic and/or cytogenetic abnormalities in the primary diagnosis. All patients with relapse should be monitored for the presence of AML.

Vaccination with live viral vaccines is not recommended for at least 2 weeks before starting blinatumomab therapy, during the course of therapy with it, and until B-lymphocyte count recovers to normal levels after the last treatment cycle.

Effect on ability to drive and use machines

Blinatumomab had a significant effect on the ability to drive and use machines. The development of confusion and disorientation, impaired coordination and balance, as well as an increased risk of seizures and impaired consciousness are possible. Due to the potential risk of neurological disorders, patients receiving Blinatumomab should refrain from driving, engaging in hazardous work or other activities, in particular, operating vehicles or working with heavy or potentially dangerous machinery.

Drug Interactions

Patients receiving drugs that affect the activity of CYP450 and transporters of substrates with a narrow therapeutic index should be monitored for the development of side effects (e.g., warfarin) or plasma concentration should be monitored (e.g., cyclosporine) during the period of concomitant use. The dose of the drug used concomitantly with blinatumomab should be adjusted.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.