Dosing and uses of Blincyto (blinatumomab)
Adult dosage forms and strengths
lyophilized powder for reconstitution
- 35mcg/vial
Acute Lymphoblastic Leukemia
Indicated for Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (total 42 days)
Allow for at least a 2 week treatment-free interval between cycles
A treatment course consists of up to 2 cycles for induction followed by 3 additional cycles for consolidation treatment (up to a total of 5 cycles)
≥45 kg
- Cycle 1: 9 mcg/day continuous IV infusion on Days 1-7, THEN 28 mcg/day on Days 8-28
- Subsequent cycles: 28 mcg/day continuous IV infusion on Days 1-28
<45 kg (BSA-based dose)
- Cycle 1: 5 mcg/m²/day (not to exceed 9 mcg/day) continuous IV infusion on Days 1-7, THEN 15 mcg/m²/day (not to exceed 28 mcg/day) on Days 8-28
- Subsequent cycles: 15 mcg/m²/day (not to exceed 28 mcg/day) on Days 1-28
Premedication
- Dexamethasone 20 mg IV 1 hr prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of ≥4 hr
Dosage modifications
If the interruption after an adverse event is ≤7 days, continue the same cycle to a total of 28 days of infusion, inclusive of days before and after the interruption in that cycle
If an interruption due to an adverse event is >7 days, start a new cycle
Cytokine release syndrome
- Grade 3: Withhold until resolved, then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur
- Grade 4: Discontinue permanently
Neurological toxicity
- Seizure: Discontinue permanently if >1 seizure occurs
- Grade 3: Withhold until ≤Grade 1 (mild) for at least 3 days, then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur; if the toxicity occurred at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg), or if the toxicity takes >7 days to resolve, discontinue permanently
- Grade 4: Discontinue permanently
Other clinically relevant adverse reactions
- Grade 3: Withhold until ≤Grade 1 (mild), then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur; if the toxicity takes >14 days to resolve, discontinue permanently
- Grade 4: Consider discontinuing permanently
Renal impairment
- Baseline CrCl ≥30 mL/min: No dose reduction required
- CrCl <30 mL/min or on hemodialysis: No information available
Hepatic impairment
- No formal pharmacokinetic studies conducted
Dosing Considerations
Approved under accelerated approval; continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials
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 reinitiation (eg, if treatment is interrupted for ≥4 hr), supervision by a healthcare professional or hospitalization is recommended
Pediatric dosage forms and strengths
lyophilized powder for reconstitution
- 35mcg/vial
Acute Lymphoblastic Leukemia
Indicated for Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (total 42 days)
Allow for at least a 2 week treatment-free interval between cycles
A treatment course consists of up to 2 cycles for induction followed by 3 additional cycles for consolidation treatment (up to a total of 5 cycles)
≥45 kg
- Cycle 1: 9 mcg/day continuous IV infusion on Days 1-7, THEN 28 mcg/day on Days 8-28
- Subsequent cycles: 28 mcg/day continuous IV infusion on Days 1-28
<45 kg (BSA-based dose)
- Cycle 1: 5 mcg/m²/day (not to exceed 9 mcg/day) continuous IV infusion on Days 1-7, THEN 15 mcg/m²/day (not to exceed 28 mcg/day) on Days 8-28
- Subsequent cycles: 15 mcg/m²/day (not to exceed 28 mcg/day) on Days 1-28
Premedication
- Dexamethasone 5 mg/m² (maximum 20 mg) IV 1 hr prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of ≥4 hr in the first cycle
Dosage modifications
If the interruption after an adverse event is ≤7 days, continue the same cycle to a total of 28 days of infusion, inclusive of days before and after the interruption in that cycle
If an interruption due to an adverse event is >7 days, start a new cycle
Cytokine release syndrome
- Grade 3: Withhold until resolved, then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur
- Grade 4: Discontinue permanently
Neurological toxicity
- Seizure: Discontinue permanently if >1 seizure occurs
- Grade 3: Withhold until ≤Grade 1 (mild) for at least 3 days, then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur; if the toxicity occurred at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg), or if the toxicity takes >7 days to resolve, discontinue permanently
- Grade 4: Discontinue permanently
Other clinically relevant adverse reactions
- Grade 3: Withhold until ≤Grade 1 (mild), then restart at 9 mcg/day (≥45 kg) or 5 mcg/m²/day (<45 kg); escalate to 28 mcg/day (≥45 kg) or 15 mcg/m²/day (<45 kg) after 7 days if the toxicity does not recur; if the toxicity takes >14 days to resolve, discontinue permanently
- Grade 4: Consider discontinuing permanently
Renal impairment
- Baseline CrCl ≥30 mL/min: No dose reduction required
- CrCl <30 mL/min or on hemodialysis: No information available
Hepatic impairment
- No formal pharmacokinetic studies conducted
Dosing Considerations
Approved under accelerated approval; continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials
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 reinitiation (eg, if treatment is interrupted for ≥4 hr), supervision by a healthcare professional or hospitalization is recommended
Blincyto (blinatumomab) adverse (side) effects
>10%
Pyrexia (62%)
Other pathogen infections (44%)
Headache (36%)
Febrile neutropenia (25%)
Nausea (25%)
Peripheral edema (25%)
Hypokalemia (23%)
Rash (21%)
Tremor (20%)
Constipation (20%)
Diarrhea (20%)
Bacterial infections (19%)
Cough (19%)
Anemia (18%)
Fatigue (17%)
Neutropenia (16%)
Dyspnea (15%)
Abdominal pain (15%)
Chills (15%)
Fungal infections (15%)
Insomnia (15%)
Dizziness (14%)
Back pain (14%)
Vomiting (13%)
Viral infections (13%)
Pain in extremity (12%)
Hypomagnesemia (12%)
Increased ALT (12%)
Increased AST (11%)
Bone pain (11%)
Hyperglycemia (11%)
Increased weight (11%)
Thrombocytopenia (11%)
Chest pain (11%)
Cytokine release syndrome (11%)
Hypotension (11%)
1-10%
Arthralgias (10%)
Decreased appetite (10%)
Leukopenia (9%)
Pneumonia (9%)
Hypertension (8%)
Sepsis (7%)
Hypophosphatemia (6%)
Warnings
Black box warnings
Cytokine release syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving blinatumomab; interrupt or discontinue depending on severity (see Dosage modifications)
Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving blinatumomab; interrupt or discontinue depending on severity (see Dosage modifications)
Contraindications
Known hypersensitivity
Cautions
Cytokine release syndrome (CRS), which may be life-threatening or fatal, has been observed and may be clinically indistinguishable from infusion reactions; serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased ALT, increased AST, and increased total bilirubin
Neurological toxicities have occurred in ~50% of patients; median time to onset of any neurological toxicity was 7 days; ≥Grade 3 (severe, life-threatening, or fatal) neurological toxicities occurred in ~15% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders
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
Tumor lysis syndrome resulting in cytokine release may occur and may be life-threatening or fatal; appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for prevention: may require either temporary interruption or discontinuation
Neutropenia and febrile neutropenia, including life-threatening cases, observed; monitor WBC and absolute neutrophil counts during infusion; interrupt if prolonged neutropenia occurs
Owing to the potential for neurologic events, including seizures, patients 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 during treatment
Transient elevation of liver enzymes reported; interrupt if the transaminases rise to >5 xULN or if bilirubin rises to >3 xULn
Leukoencephalopathy observed confirmed by cranial MRI, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (high dose methotrexate, IT cytarabine); clinical significance of this is unknown
Preparation and administration errors have occurred; follow instructions for preparation (including admixing) and administration strictly to minimize medication errors
Potential for immunogenicity (as with all therapeutic proteins)
Possible drug interactions
- No formal drug interaction studies have been conducted Initiation of blinatumomab 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
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown if distributed in human breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Blincyto (blinatumomab)
Mechanism of action
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
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, up-regulation 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
Absorption
Steady-state achieved within a day of continuous IV infusion
Mean concentration at steady-state: 211 pg/mL (9 mcg/day); 621 pg/mL (28 mcg/day)
Distribution
Vd: 4.52 L
Metabolism
Metabolic pathway has not been characterized
Like other protein therapeutics, it is expected to be degraded into small peptides and amino acids via catabolic pathways
Elimination
Half-life: 2.11 hr
Systemic clearance: 2.92 L/hr
Excretion: Negligible amounts in urine (all doses)
Administration
IV Preparation
Reconstituting viaL
- Using a 5-mL syringe, reconstitute 1 vial using 3 mL of preservative-free sterile water for injection
- Direct sterile water for injection toward the side of the vial during reconstitution
- Gently swirl contents to avoid excess foaming
- Do not shake
IV admixture
- Specific admixing instructions are provided for each dose and infusion time
- Preparation of prefilled 250 mL of 0.9% NaCl IV bag is needed, including volume adjustment and transferring IV solution stabilizer to the bag
- See prescribing information for specific instructions for preparation
IV Administration
Prime the IV line only with the prepared solution for infusion
Do not prime with 0.9% NaCL
Premedicate with dexamethasone 20 mg IV 1 hr prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of ≥4 hr
Administer as a continuous IV infusion at a constant flow rate using an infusion pump; the pump should be programmable, lockable, non-elastomeric, and have an alarm
Infusion bags should be infused over 24 hr or 48 hr (see preparation)
Infuse the total 240 mL solution according to the instructions on the pharmacy label on the bag at one of the following constant infusion rates:
-Infusion rate of 10 mL/hr for a duration of 24 hr, Or
-Infusion rate of 5 mL/hr for a duration of 48 hr
The solution for infusion must be administered using IV tubing that contains a sterile, nonpyrogenic, low protein-binding, 0.2 micron in-line filter
Infuse through a dedicated lumen
At the end of the infusion, any unused solution in the IV bag and IV lines should be disposed of in accordance with local requirements
Do NOT flush line
- Do not flush the infusion line, especially when changing infusion bags
- Flushing when changing bags or at completion of infusion can result in excess dosage
Storage
Protect from light
Reconstituted viaL
- Room temperature 23- 27°C (73-81°F): 4 hr
- Refrigerated 2-8°C (36-46°F): 24 hr
Prepared IV bag with stabilizer
- Room temperature 23- 27°C (73-81°F): 48 hr (includes infusion time)
- Refrigerated 2-8°C (36-46°F): 8 days
