Blinatumomab

Registered South African indications:

• MRD-positive B-cell precursor acute lymphoblastic leukaemia (ALL)
  - In first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0,1 %
• Relapsed or refractory B-cell precursor ALL

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding

Cautions

South African manufacturer recommendations

• Pregnancy
• Women of childbearing potential
• Severe renal impairment
• Severe hepatic impairment
• Elderly
• Active ALL in the central nervous system
• History or presence of clinically relevant CNS pathology
• Prior treatment with cranial irradiation and anti-leukemic chemotherapy (including systemic high dose methotrexate or intrathecal cytarabine)
• Medication errors
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential
• Severe renal impairment
• Severe hepatic impairment
• Elderly (≥75 years)
• Risk of neurological events
• Medical history of neurologic signs and symptoms
  - Dizziness
  - Hypoaesthesia
  - Hyporeflexia
  - Tremor
  - Dysaesthesia
  - Paraesthesia
  - Memory impairment
• History or presence of clinically relevant CNS pathology
  - Epilepsy
  - Seizures
  - Paresis
  - Aphasia
  - Stroke
  - Severe brain injuries
  - Dementia
  - Parkinson's disease
  - Cerebellar disease
  - Organic brain syndrome
  - Psychosis
•  Active ALL in the CNS or cerebrospinal fluid
•  Active uncontrolled infection
•  Eastern Cooperative Oncology Group (ECOG) performance status at baseline of 2
• Prior treatment with cranial irradiation and anti-leukemic chemotherapy (including systemic high dose methotrexate or intrathecal cytarabine)
• Medication errors
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment should be initiated under the direction of and supervision by physicians experienced in the treatment of haematological malignancies

Used for the treatment of

• MRD-positive B-cell precursor acute lymphoblastic leukaemia (ALL)
  - In first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%
• Relapsed or refractory B-cell precursor ALL

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For the treatment of MRD-positive B-cell precursor ALL, hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended

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For the treatment of relapsed or refractory B-cell precursor ALL, hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended

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See additional prescribing points for premedication and method of administration

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Consult specialist for dosages and regimens

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International manufacturer recommendations

Treatment should be initiated under the direction of and supervision by physicians experienced in the treatment of haematological malignancies

Used for the treatment of

• CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL)
  - Philadelphia chromosome positive B-precursor ALL who have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and have no alternative treatment options
• Philadelphia chromosome negative CD19 positive B-precursor ALL
  - In first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%

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For the treatment of relapsed or refractory B-precursor ALL, hospitalisation is recommended for initiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle

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For the treatment of Philadelphia chromosome negative MRD positive B-precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles

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In patients with a history or presence of clinically relevant central nervous system (CNS) pathology, hospitalisation is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance to blinatumomab in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events have been observed

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For all subsequent cycle starts and reinitiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalisation is recommended

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Consult specialist for dosages and regimens

Paed. forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment should be initiated under the direction of and supervision by physicians experienced in the treatment of haematological malignancies

Used for the treatment of

MRD-positive B-cell precursor acute lymphoblastic leukaemia (ALL)
- In first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%

Younger than 1 month

• No information available

1 month and older

• Consult specialist for dosages and regimens

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Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended

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For premedication with dexamethasone for relapsed or refractory B-cell precursor ALL, see additional prescribing points

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Consult specialist for dosages and regimens

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International manufacturer recommendations

Treatment should be initiated under the direction of and supervision by physicians experienced in the treatment of haematological malignancies

Used for the treatment of

Philadelphia chromosome negative CD19 positive B-precursor acute lymphoblastic leukaemia (ALL)
- Refractory or in relapse after receiving at least two prior therapies
- In relapse after receiving prior allogeneic haematopoietic stem cell transplantation
- High-risk first relapsed as part of the consolidation therapy

Younger than 1 year

• Not established for use

1 year and older

• Consult specialist for dosages and regimens

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For paediatric patients with high-risk first relapsed B-precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the cycle

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For the treatment of relapsed or refractory B-precursor ALL, hospitalisation is recommended for initiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle

---

For the treatment of Philadelphia chromosome negative MRD positive B-precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles

---

In patients with a history or presence of clinically relevant central nervous system (CNS) pathology, hospitalisation is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance to blinatumomab in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events have been observed

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For all subsequent cycle starts and reinitiation (e.g. if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalisation is recommended

---

Consult specialist for dosages and regimens

Pregnancy

South African manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• Based on its mechanism of action, blinatumomab may cause foetal harm including B-cell lymphocytopenia when administered to a pregnant woman
• There are no data on the use of blinatumomab in pregnant women
• In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier
• Advise pregnant women of the potential risk to a foetus
• The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively
• Animal reproduction studies have not been conducted with blinatumomab
• In embryo-foetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-foetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in foetuses
• Due to the potential for depletion of B lymphocytes in infants following exposure to blinatumomab during pregnancy, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination
• Live virus vaccines can be administered when the B lymphocytes are within the normal range
• Women of childbearing potential should use contraception during and for at least 48 hours after treatment with blinatumomab

International manufacturer recommendations

• Caution; not recommended
• Reproductive toxicity studies have not been conducted with blinatumomab
• In an embryo-foetal developmental toxicity study conducted in mice, the murine surrogate molecule crossed the placenta and did not induce embryotoxicity, or teratogenicity
• The expected depletions of B-and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses
• There are no data from the use of blinatumomab in pregnant women
• Blinatumomab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus
• Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab
• In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to the pharmacological properties of the agent. Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production
• Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from blinatumomab, including B-cell lymphocytopenia, advise patients not to breastfeed during and for at least 48 hours after treatment with blinatumomab

International manufacturer recommendations

• Contraindicated 
• It is unknown whether blinatumomab or metabolites are excreted in human milk
• Based on its pharmacological properties, a risk to the breastfeeding child cannot be excluded
• Consequently, as a precautionary measure, breastfeeding is contraindicated during and for at least 48 hours after treatment with blinatumomab

Fertility

• No studies have been conducted to evaluate the effects of blinatumomab on fertility
• No adverse effects on male or female mouse reproductive organs in 13 week toxicity studies with the murine surrogate molecule

Renal Impairment

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; no information available 
  The safety and efficacy of blinatumomab have not been studied in patients with severe renal impairment

Hepatic Impairment

• No dose adjustment recommended 
  Based on pharmacokinetic analyses, no effect of baseline liver function on blinatumomab exposure is expected and adjustment of the initial dose is not necessary
• Severe: Caution; no information available 
  The safety and efficacy of blinatumomab have not been studied in patients with severe hepatic impairment

Elderly

South African manufacturer recommendations

• Caution; no dose adjustment recommended 
  No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients
  Elderly patients experienced a higher rate of serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion

International manufacturer recommendations

• ≥65 years: No dose adjustment recommended 
• ≥75 years: Caution; no dose adjustment recommended 
  There is limited experience with blinatumomab in patients ≥75 years of age
  Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy, and confusion

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
• Tremor
• Confusional state
• Disorientation
• Encephalopathy
  - Leukoencephalopathy
• Aphasia
• Paraesthesia
• Seizure
• Cognitive disorder
• Memory impairment
• Dizziness
• Somnolence
• Hypoaesthesia
• Cranial nerve disorder
• Ataxia
• Speech disorder
• Neurologic events (including fatal outcome)

Cardiovascular Disorders

• Tachycardia
  -Sinus tachycardia
  - Supraventricular tachycardia
  - Atrial tachycardia
  - Ventricular tachycardia
• Hypotension
• Hypertension
• Flushing
• Capillary leak syndrome

Respiratory Disorders

• Cough
  - Productive cough
• Dyspnoea
  - Exertional dyspnoea
• Respiratory failure
  - Acute respiratory failure
• Wheezing
• Chest pain
  - Chest discomfort
  - Non-cardiac chest pain
• Pulmonary oedema
• Pneumonia

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Abdominal pain
• Pancreatitis (including life-threatening or fatal outcomes)
  (See additional prescribing points)
• Laryngeal oedema

Hepatobiliary Disorders

• Increased hepatic enzymes
  - Alanine aminotransferase
  - Aspartate aminotransferase
  - Gamma-glutamyl transferase
  - Transaminases
  - Blood alkaline phosphatase
  (See additional prescribing points)
• Hyperbilirubinaemia

Genitourinary Disorders

• Oedema
  - Oedematous kidney
  - Scrotal oedema
  - Genital oedema

Endocrine and Metabolic Disorders

• Tumour lysis syndrome (including life-threatening or fatal outcomes)
  (See additional prescribing points)
• Increased weight

Musculoskeletal Disorders

• Back pain
• Pain in extremity
• Bone pain
• Bone marrow oedema
• Musculoskeletal chest pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Erythema
  - Erythematous rash
  - Generalised rash
  - Macular rash
  - Maculopapular rash
  - Pruritic rash
  - Catheter site rash
  - Pustular rash
  - Genital rash
  - Papular rash
  - Vesicular rash
• Angioedema
  - Circumoral oedema
  - Face oedema

Immune, Blood and Lymphatic System Disorders

• Infections (including life-threatening or fatal outcomes)
  - Viral infections
  - Bacterial infections
  - Bacteraemia
  - Unspecified pathogen
  - Sepsis
  - Fungal infections
  - Opportunistic infections
  - Catheter site infections
  (See additional prescribing points)
• Febrile neutropenia (including life-threatening cases)
  (See additional prescribing points)
• Anaemia
• Neutropenia
• Thrombocytopenia
• Leukopenia
• Pyrexia
• Chills
• Oedema
  - Generalised oedema
  - Localised oedema
  - Peripheral oedema
  - Infusion site oedema
  - Lip oedema
  - Lymphoedema
• Cytokine release syndrome (including life-threatening or fatal outcomes)
  - Cytokine storm
  (See additional prescribing points)
• Infusion related reactions
  - Pyrexia
  - Cytokine release syndrome (including life-threatening or fatal outcomes)
  - Hypotension
  - Myalgia
  - Acute renal injury
  - Hypertension
  - Rash
  - Tachypnea
  - Face swelling
  - Face oedema
  - Erythematous rash
• Decreased immunoglobulins
  - Blood immunoglobulin G
  - Blood immunoglobulin A
  - Blood immunoglobulin M
  - Globulins
• Hypogammaglobulinaemia
• Hypoglobulinaemia
• Leukocytosis
• Lymphopenia
• Hypersensitivity
• Lymphadenopathy
• Haematophagic histiocytosis
• Development of anti-blinatumomab antibodies

Sensory Disorders

• Oedema
  - Periorbital oedema
  - Eyelid oedema
  - Eye oedema

Others

• Pain

• Live viral vaccines
• Warfarin
• Cyclosporin

• Full blood count with differential
• Hepatic function
• Hepatitis B virus screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Pregnancy status

Additional observations

• Signs and symptoms of
  - Cytokine release syndrome
  - Infusion reactions
  - Neurotoxicity
  - Infection
  - Pancreatitis
  - Tumor lysis syndrome

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Premedication with prednisone or equivalent for MRD-positive B-cell precursor ALL

• For adult patients, premedicate with prednisone 100mg intravenously or equivalent (e.g., dexamethasone 16mg) 1 hour prior to the first dose of blinatumomab in each cycle
• For paediatric patients, premedicate with 5mg/m² of dexamethasone, to a maximum dose of 20mg prior to the first dose of blinatumomab in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle

Premedication with dexamethasone for relapsed or refractory B-cell precursor ALL

• For adult patients, premedicate with 20mg dexamethasone 1 hour prior to the first dose of blinatumomab of each cycle, prior to a step dose (such as cycle 1 day 8), and when restarting an infusion after an interruption of 4 or more hours
• For paediatric patients, premedicate with 5mg/m² of dexamethasone, to a maximum dose of 20mg prior to the first dose of blinatumomab in the first cycle, prior to a step dose (such as cycle 1 day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle

General method of reconstitution and preparation of solution for infusion

• It is very important that the instructions for preparation (including admixing) and administration are strictly followed to minimize medication errors (including under-dosing and overdosing)
• Blinatumomab can be infused over 24 or 48 hours. The choice between these options for the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes and the weight of the patient
• Strictly observe aseptic technique when preparing the solution for infusion since blinatumomab vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare blinatumomab according to aseptic standards, including but not limited to
  - Prepare blinatumomab in a USP <797> compliant facility
  - Prepare blinatumomab in an ISO Class 5 laminar flow hood or better
  - Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring
  - Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs
  - Ensure that personnel wear appropriate protective clothing and gloves
  - Ensure that gloves and surfaces are disinfected
•  1 package blinatumomab includes 1 vial of blinatumomab and 1 vial of IV solution stabiliser
• DO NOT use the IV solution stabilizer for reconstitution of blinatumomab. The IV solution stabilizer is provided with the blinatumomab package and is used to coat the IV bag prior to addition of reconstituted blinatumomab to prevent adhesion of blinatumomab to IV bags and IV tubing
• More than 1 package of blinatumomab may be needed to prepare some of the prescribed doses
• Add 3ml of preservative-free sterile water for injection, by directing the water along the walls of the blinatumomab vial and not directly on the lyophilized powder (resulting in a final blinatumomab concentration of 12.5µg/ml)
• Gently swirl contents to avoid excess foaming. DO NOT SHAKE
• Visually inspect the reconstituted solution for particulate matter and discolouration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colourless to slightly yellow. Do not use if solution is cloudy or has precipitated

Specific method of preparation of infusion bag for 24 or 48 hour infusion

• Verify the prescribed dose and infusion duration for each blinatumomab infusion bag
• Aseptically add 270ml 0.9% sodium chloride injection, USP to the IV bag
• Aseptically transfer 5.5ml IV solution stabilizer to the IV bag containing 0.9% sodium chloride injection, USP
• Gently mix the contents of the bag to avoid foaming
• Discard the vial containing the unused IV solution stabiliser
• Aseptically transfer reconstituted blinatumomab into the IV bag containing 0.9% sodium chloride injection, USP and IV solution stabiliser
• Gently mix the contents of the bag to avoid foaming
• Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter
• Ensure that the IV tubing is compatible with the infusion pump
• Remove air from the IV bag. This is particularly important for use with an ambulatory infusion pump
• Prime the IV tubing only with the prepared solution for infusion. Do not prime with 0.9% sodium chloride injection, USP
• Store at 2°C to 8°C if not used immediately
• Maximum storage time of reconstituted blinatumomab vial
  - Room temperature 23°C to 27°C: 4 hours
  - Refrigerated 2°C to 8°C: 24 hours
• Maximum storage time of prepared blinatumomab infusion bag
  - Room temperature 23°C to 27°C: 48 hours
  - Refrigerated 2°C to 8°C: 8 days

Cytokine release syndrome and infusion reactions

• Cytokine release syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving blinatumomab
• The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved
• Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC)
• The manifestations of CRS after treatment with blinatumomab overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/ macrophage activation syndrome (MAS)
• Using all of these terms to define CRS in clinical trials of blinatumomab, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL
• Monitor patients for signs or symptoms of these events. Advise outpatients on blinatumomab to contact their healthcare professional for signs and symptoms associated with CRS
• If severe CRS occurs, interrupt blinatumomab until CRS resolves
• Discontinue blinatumomab permanently if life-threatening CRS occurs
• Administer corticosteroids for severe or life-threatening CRS

Tumour lysis syndrome

• Tumour lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving blinatumomab
• Appropriate prophylactic measures, including pre-treatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during blinatumomab treatment. Monitor for signs or symptoms of TLS
• Management of these events may require either temporary interruption or discontinuation of blinatumomab

Infections

• In patients with ALL receiving blinatumomab in clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal
• As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with blinatumomab
• Monitor patients for signs and symptoms of infection and treat appropriately

Neutropenia and febrile neutropenia

• Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving blinatumomab
• Laboratory parameters (including, but not limited to white blood cell count and absolute neutrophil count) should be monitored routinely during blinatumomab infusion and treated appropriately
• Interrupt blinatumomab if prolonged neutropenia occurs

Elevated liver enzymes

• Treatment with blinatumomab was associated with transient elevations in liver enzymes
• In patients with ALL receiving blinatumomab in clinical studies, the median time to onset of elevated liver enzymes was 3 days
• The majority of these transient elevations in liver enzymes were observed in the setting of CRS. For the events that were observed outside the setting of CRS, the median time to onset was 19 days
• Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients
• Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during blinatumomab treatment
• Interrupt blinatumomab if the transaminases rise to greater than 5 times the upper limit of normal or if total bilirubin rises to more than 3 times the upper limit of normal

Pancreatitis

• Fatal pancreatitis has been reported in patients receiving blinatumomab in combination with dexamethasone in clinical studies and the post-marketing setting
• Patients should be closely monitored for signs and symptoms of pancreatitis
• Evaluate patients who develop signs and symptoms of pancreatitis
• Management of pancreatitis may require either temporary interruption or discontinuation of blinatumomab
  01 Sept 2023

Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.

Injection (per vial) 38.5µg

• Blincyto (Amgen) originator