BLINCYTO® (blinatumomab) for injection

BLINCYTO® (blinatumomab) for injection

Share this
Advertisement

BLINCYTO® (blinatumomab) for injection

BLINCYTO (blinatumomab) is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 (expressed on cells of B-lineage origin) and CD3 (expressed on T cells). BLINCYTO is produced in Chinese hamster ovary cells. It consists of 504 amino acids and has a molecular weight of approximately 54 kilodaltons.

Each BLINCYTO package contains 1 vial BLINCYTO and 1 vial IV Solution Stabilizer.

BLINCYTO is supplied in a single-dose vial as a sterile, preservative-free, white to off-white lyophilized powder for intravenous administration. Each single-dose vial of BLINCYTO contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust pH to 7.0. After reconstitution with 3 mL of preservative-free Sterile Water for Injection, USP, the resulting concentration is 12.5 mcg/mL blinatumomab.

IV Solution Stabilizer is supplied in a single-dose vial as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each single-dose vial of IV Solution Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride (2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and water for injection.

Indications and usage

BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

Mechanism of Action

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds 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. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.

Dosage and administration

  • A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
  • Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).
  • A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
  • A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).
CycleGreater than or equal to 45 kg (fixed-dose)Less than 45 kg (BSA-based dose)
Induction Cycle 1 Days 1-7

Days 8-28

Days 29-42

9 mcg/day

28 mcg/day

14-day treatment-free interval

5 mcg/m2 /day (not to exceed 9 mcg/day)
15 mcg/m2 /day (not to exceed 28 mcg/day)
14-day treatment-free interval
Induction Cycle 2 Days 1-28

Days 29-42

28 mcg/day

14-day treatment-free interval

15 mcg/m2 /day (not to exceed 28 mcg/day)
14-day treatment-free interval
Consolidation Cycles 3-5 Days 1-28

Days 29-42

28 mcg/day

14-day treatment-free interval

15 mcg/m2 /day (not to exceed 28 mcg/day)
14-day treatment-free interval
Continued Therapy Cycles 6-9 Days 1-28
28 mcg/day

14-day treatment-free interval

15 mcg/m2 /day (not to exceed 28 mcg/day)
14-day treatment-free interval

Special Considerations

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.

Premedicate with dexamethasone.

  • For adult patients, premedicate with 20 mg dexamethasone 1 hour prior to the first dose of BLINCYTO 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 pediatric patients, premedicate with 5 mg/m2 of dexamethasone, to a maximum dose of 20 mg prior to the first dose of BLINCYTO 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.

Adverse reactions

The most common adverse reactions (≥ 20%) were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia.

Contraindications

BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and precautions

Cytokine Release Syndrome

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO.

Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS.

Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was reported in patients receiving BLINCYTO.

Neurological Toxicities: Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended

Infections: In patients with ALL receiving BLINCYTO 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 BLINCYTO.

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

Advertisement

Neutropenia and Febrile Neutropenia: Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Treatment with BLINCYTO was associated with transient elevations in liver enzymes. In patients with ALL receiving BLINCYTO in clinical studies, the median time to onset of elevated liver enzymes was 3 days.

Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting

Leukoencephalopathy: Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.

Immunization: The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.

Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including BLINCYTO (with preservative). The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

Drug interactions

No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine). Adjust the dose of the concomitant drug as needed.

Use in specific populations

Pregnancy: Based on its mechanism of action, BLINCYTO may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman. There are no data on the use of BLINCYTO 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 fetus.

Due to the potential for B-cell lymphocytopenia in infants following exposure to BLINCYTO in-utero, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination

Lactation: 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 nursing infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during and for at least 48 hours after treatment with BLINCYTO.

Contraception: Advise females of reproductive potential to use effective contraception during treatment and for at least 48 hours after the last dose of BLINCYTO.

Pediatric Use: The safety and efficacy of BLINCYTO have been established in pediatric patients. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups.

Geriatric Use: Of the total number of patients with relapsed or refractory ALL in clinical studies of BLINCYTO, treated at the recommended dose and schedule, approximately 12% were 65 and over, while 3% were 75 and older. 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. However, elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections

Overdosage

Overdoses have been observed, including one adult patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration.

In the dose evaluation phase of the Phase ½ study in pediatric and adolescent patients with relapsed or refractory B-cell precursor ALL, one patient experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS) at a 30 mcg/m2 /day (higher than the maximum tolerated/recommended) dose

Overdoses resulted in adverse reactions, which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care. Consider re-initiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion

Advertisement
Share this

Leave a Reply