Blinatumomab (Monograph)

Brand name: Blincyto
Drug class: Antineoplastic Agents
- Bispecific T-cell Engager
- BiTE
Chemical name: Anti-(human CD3 (antigen)) (clone 1 single-chain) anti-(human CD19 (antigen)) (single-chain) fusion protein with immunoglobulin immunoglobulin
Molecular formula: C₂₃₆₇H₃₅₇₇N₆₄₉O₇₇₂S₁₉
CAS number: 853426-35-4

Medically reviewed by Drugs.com on Jan 31, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a CD3 T-cell-engaging anti-CD19 monoclonal antibody.

Uses for Blinatumomab

Philadelphia Chromosome-Negative Precursor B-Cell Acute Lymphoblastic Leukemia (pre-B-ALL)

Treatment of Philadelphia chromosome-negative (Ph^-) relapsed or refractory pre-B-ALL (designated an orphan drug by FDA for this use). Efficacy determined based on complete remission (CR) or complete remission with partial hematologic recovery (CRh) within the first 2 treatment cycles in a noncomparative, open-label, phase 2 study in patients with Ph^- relapsed or refractory pre-B-ALL.

Continued approval may be contingent on verification of clinical benefit in confirmatory studies.

Blinatumomab Dosage and Administration

General

• Administer blinatumomab in a hospital setting on days 1–9 of cycle 1 and days 1–2 of cycle 2. During initiation of all subsequent cycles and for reinitiation of therapy (i.e., following interruption lasting ≥4 hours), manufacturer recommends administering the drug under clinician supervision or in a hospital setting.

• Premedicate with dexamethasone 20 mg IV 1 hour before first infusion of blinatumomab in each cycle, prior to a dosage escalation (i.e., from 9 mcg daily to 28 mcg daily), and when reinitiating therapy following an interruption lasting ≥4 hours.

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by continuous IV infusion.

Blinatumomab powder for injection must be reconstituted and diluted prior to administration. (See Storage under Stability.)

May administer using a programmable, non-elastomeric ambulatory infusion pump equipped with an alarm and locking mechanism.

Administer through a sterile, nonpyrogenic, low-protein-binding 0.2-µm inline filter. Use polyolefin, non-diethylhexylphthalate (non-DEHP) plasticized PVC, or ethyl vinyl acetate (EVA) infusion bags or pump cassettes and administration sets.

Remove any air remaining in the infusion bag and prime administration set tubing with the final diluted solution of blinatumomab. Do not prime with 0.9% sodium chloride injection.

Administer through a dedicated lumen. Do not flush the IV administration line following blinatumomab infusion or when changing IV bags; flushing may result in the patient receiving an excess dose.

Discard any unused portion in the vial, infusion bag, or administration set tubing.

Preparation and Administration Precautions

Proper procedures for preparing a final blinatumomab infusion solution from the reconstituted solution vary according to dosage (9 or 28 mcg daily), infusion time for the IV bag (24 or 48 hours), and infusion rate (5 or 10 mL/hour). Consult manufacturer’s labeling for detailed information on preparation of blinatumomab. (See Preparation and Administration Errors under Cautions.)

The manufacturer-provided IV solution stabilizer is added to the infusion bag prior to addition of the reconstituted blinatumomab solution to minimize adsorption of the drug to the infusion bag and administration set tubing. Do not use the IV solution stabilizer to reconstitute blinatumomab powder for injection. Solution stabilizer contains citric acid monohydrate, lysine hydrochloride, polysorbate 80, and sodium hydroxide (to adjust pH to 7) in sterile water for injection.

Instructions for preparation of final diluted blinatumomab solutions for IV infusion account for an overfill of 15–25 mL (total volume of 265–275 mL) in 250-mL prefilled infusion bags; if necessary, adjust volume of the prefilled infusion bag to achieve an initial volume of 265–275 mL prior to adding the solution stabilizer.

Reconstitution and Dilution for Administration of Blinatumomab 9 mcg Daily at an IV Infusion Rate of 10 mL/hour for 24 Hours

Add 5.5 mL of the IV solution stabilizer to a 250-mL infusion bag containing 0.9% sodium chloride injection. Prefilled infusion bag should contain an overfill of 15–25 mL (total volume of 265–275 mL); if necessary, adjust volume of the prefilled infusion bag to achieve an initial volume of 265–275 mL prior to adding the solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitute vial containing 35 mcg of blinatumomab with 3 mL of preservative-free sterile water for injection to provide a solution containing 12.5 mcg/mL; direct diluent toward the wall of the vial. Gently swirl vial to avoid excess foaming. Do not shake reconstituted solution.

Add 0.83 mL of reconstituted blinatumomab solution to the 250-mL prefilled infusion bag containing 265–275 mL of 0.9% sodium chloride injection and IV solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitution and Dilution for Administration of Blinatumomab 9 mcg Daily at an IV Infusion Rate of 5 mL/hour for 48 Hours

Add 5.5 mL of the IV solution stabilizer to a 250-mL infusion bag containing 0.9% sodium chloride injection. Prefilled infusion bag should contain an overfill of 15–25 mL (total volume of 265–275 mL); if necessary, adjust volume of the prefilled infusion bag to achieve an initial volume of 265–275 mL prior to adding the solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitute vial containing 35 mcg of blinatumomab with 3 mL of preservative-free sterile water for injection to provide a solution containing 12.5 mcg/mL; direct diluent toward the wall of the vial. Gently swirl vial to avoid excess foaming. Do not shake reconstituted solution.

Add 1.7 mL of reconstituted blinatumomab solution to the 250-mL prefilled infusion bag containing 265–275 mL of 0.9% sodium chloride injection and IV solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitution and Dilution for Administration of Blinatumomab 28 mcg Daily at an IV Infusion Rate of 10 mL/hour for 24 Hours

Add 5.6 mL of the IV solution stabilizer to a 250-mL infusion bag containing 0.9% sodium chloride injection. Prefilled infusion bag should contain an overfill of 15–25 mL (total volume of 265–275 mL); if necessary, adjust volume of the prefilled infusion bag to achieve an initial volume of 265–275 mL prior to adding the solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitute vial containing 35 mcg of blinatumomab with 3 mL of preservative-free sterile water for injection to provide a solution containing 12.5 mcg/mL; direct diluent toward the wall of the vial. Gently swirl vial to avoid excess foaming. Do not shake reconstituted solution.

Add 2.6 mL of reconstituted blinatumomab solution to the 250-mL prefilled infusion bag containing 265–275 mL of 0.9% sodium chloride injection and IV solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitution and Dilution for Administration of Blinatumomab 28 mcg Daily at an IV Infusion Rate of 5 mL/hour for 48 Hours

Add 5.6 mL of the IV solution stabilizer to a 250-mL infusion bag containing 0.9% sodium chloride injection. Prefilled infusion bag should contain an overfill of 15–25 mL (total volume of 265–275 mL); if necessary, adjust volume of the prefilled infusion bag to achieve an initial volume of 265–275 mL prior to adding the solution stabilizer. Gently mix infusion bag to avoid foaming.

Reconstitute 2 vials, each containing 35 mcg of blinatumomab powder for injection. Reconstitute each vial with 3 mL of preservative-free sterile water for injection to provide a solution containing 12.5 mcg/mL; direct diluent toward the wall of the vial. Gently swirl vial to avoid excess foaming. Do not shake reconstituted solution.

Add total of 5.2 mL of reconstituted blinatumomab solution (2.7 mL from one vial and 2.5 mL from the other vial) to the 250-mL prefilled infusion bag containing 265–275 mL of 0.9% sodium chloride injection and IV solution stabilizer. Gently mix infusion bag to avoid foaming.

Rate of Administration

Administer by continuous IV infusion at rate that delivers the intended dosage (9 mcg daily or 28 mcg daily). Infusion rate (in mL/hour) depends on the specific reconstitution and dilution procedure used to prepare the final infusion solution.

Dosage

Adults

Ph- Pre-B-ALL in Adults Weighing ≥45 kg

IV

Cycle 1: 9 mcg daily on days 1–7, followed by 28 mcg daily on days 8–28, then followed by a 2-week rest period.

Subsequent cycles: 28 mcg daily on days 1–28 of each 6-week treatment cycle.

Treatment course consists of induction therapy with blinatumomab for up to 2 cycles followed by consolidation therapy for 3 additional cycles (total of up to 5 cycles).

Dosage Modification for Toxicity

If interruption of therapy is required for ≤7 days, continue current cycle for a total of 28 days (including the treatment days prior to and after the interruption).

If therapy is interrupted for >7 days, initiate a new cycle.

Grade 3 or 4 Toxicity

IV

If grade 3 toxicity occurs, interrupt therapy until toxicity resolves to grade 0 or 1; resume therapy at reduced dosage of 9 mcg daily if the toxicity resolves in ≤14 days. Dosage may be re-escalated to 28 mcg daily if the toxicity does not recur within 7 days.

If the toxicity persists for >14 days following interruption of therapy, permanently discontinue blinatumomab therapy.

If grade 4 toxicity occurs, consider permanently discontinuing blinatumomab therapy.

Cytokine Release Syndrome

IV

If grade 3 cytokine release syndrome occurs, interrupt therapy until toxicity resolves; resume therapy at reduced dosage of 9 mcg daily. Dosage may be re-escalated to 28 mcg daily if the toxicity does not recur within 7 days.

If grade 4 cytokine release syndrome occurs, permanently discontinue blinatumomab therapy.

Neurologic Toxicity

IV

If grade 3 neurologic toxicity occurs, interrupt therapy until toxicity resolves to grade 0 or 1 for ≥3 days; resume therapy at reduced dosage of 9 mcg daily. Dosage may be re-escalated to 28 mcg daily if the toxicity does not recur within 7 days.

If neurologic toxicity occurs at a dosage of 9 mcg daily or persists for >7 days following interruption of therapy, permanently discontinue blinatumomab therapy.

If >1 seizure occurs or if grade 4 neurologic toxicity occurs, permanently discontinue blinatumomab therapy.

Special Populations

Hepatic Impairment

Not studied; no specific dosage recommendations at this time.

Renal Impairment

Cl_cr ≥30 mL/minute: No dosage adjustment required. (See Special Populations under Pharmacokinetics.)

Cl_cr <30 mL/minute and patients receiving hemodialysis: No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Related/similar drugs

methotrexate, doxorubicin, imatinib, mercaptopurine, Gleevec, Sprycel

Cautions for Blinatumomab

Contraindications

• Known hypersensitivity to blinatumomab or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cytokine Release Syndrome

Cytokine release syndrome, sometimes life-threatening or fatal, reported; peak cytokine release observed within 2 days following initiation of blinatumomab.

Serious adverse effects associated with cytokine release syndrome include pyrexia, headache, nausea, asthenia, hypotension, and elevated ALT, AST, and bilirubin concentrations; most patients in clinical studies did not require discontinuance of therapy. Disseminated intravascular coagulation, capillary leak syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome also reported. Infusion-related reactions may be clinically indistinguishable from manifestations of cytokine release syndrome.

Closely monitor patients for signs and symptoms of cytokine release syndrome. (See Advice to Patients.) Interruption or discontinuance of therapy may be necessary. (See Cytokine Release Syndrome under Dosage and Administration.)

Neurologic Toxicity

Neurologic toxicities occur commonly; median time to onset is 7 days. Severe, life-threatening, or fatal toxicity (e.g., encephalopathy, seizures, speech impairment, disturbances in consciousness, confusion and disorientation, coordination and balance disorders) can occur. Patients should not drive a motor vehicle or engage in hazardous occupations or activities (e.g., operating hazardous machinery) while receiving the drug.

Neurologic toxicity generally resolves following treatment interruption; however, discontinuance of therapy may be necessary. In the principal efficacy study, grade 1 or 2 neurologic toxicities were managed with dexamethasone without treatment interruption.

Monitor patients for manifestations of neurologic toxicities. (See Advice to Patients.) Interruption or discontinuance of therapy may be necessary. (See Neurologic Toxicity under Dosage and Administration.)

Other Warnings and Precautions

Infectious Complications

Serious infections (e.g., sepsis, pneumonia, bacteremia, opportunistic infections, catheter-site infections), sometimes life-threatening or fatal, reported.

Initiate prophylactic anti-infective therapy as appropriate and employ surveillance testing during blinatumomab therapy. Monitor patients for signs and symptoms of infection; initiate appropriate anti-infective treatment as clinically indicated.

Tumor Lysis Syndrome

Tumor lysis syndrome, sometimes life-threatening or fatal, reported.

Monitor patients for signs and symptoms of tumor lysis syndrome; interruption or discontinuance of blinatumomab therapy may be necessary. Initiate appropriate prophylactic measures (e.g., pretreatment nontoxic cytoreduction, adequate hydration during therapy).

Neutropenia and Febrile Neutropenia

Neutropenia and febrile neutropenia, sometimes life-threatening, reported.

Monitor CBC, including differential. If prolonged neutropenia occurs, interrupt therapy.

Hepatic Effects

Transient increases in hepatic enzyme concentrations reported; median time to onset is 15 days. Mostly occurs in association with cytokine release syndrome.

Evaluate serum ALT, AST, γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), and total bilirubin concentrations prior to and during blinatumomab therapy. If ALT and/or AST concentrations >5 times the ULN or total bilirubin concentrations >3 times the ULN occur, interrupt blinatumomab therapy.

Leukoencephalopathy

Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy reported, particularly in those who previously received cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical importance of these changes is not known.

Preparation and Administration Errors

Medication errors resulting in underdosage or overdosage of blinatumomab have occurred. Exercise extra care to ensure proper preparation and administration of the drug. (See Preparation and Administration Precautions under Dosage and Administration.)

Immunogenicity

Antibodies to blinatumomab, including neutralizing antibodies to the drug, reported. Pharmacokinetics may be affected. No clinically important effects on safety observed to date.

Specific Populations

Pregnancy

Category C.

May cause fetal harm, including B-cell lymphocytopenia. Embryofetal toxicity and teratogenicity not observed in animal studies; however, the surrogate molecule crossed the placenta. B-cell and T-cell depletion occurred in pregnant mice; however, hematologic effects were not assessed in fetuses.

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Not known whether blinatumomab is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Limited experience in pediatric patients.

Dose-limiting toxicity was cytokine release syndrome in pediatric patients (2–17 years of age) with relapsed or refractory pre-B-ALL; incidence decreased with stepwise dosing of blinatumomab (5 mcg/m² daily initially for 7 days, then 15 mcg/m² daily). Fatal respiratory failure and grade 4 cytokine release syndrome resulting in fatal cardiac failure and life-threatening GI hemorrhage reported following administration of blinatumomab 15–30 mcg/m² daily.

Pharmacokinetic parameters similar to those reported in adults with relapsed or refractory pre-B-ALL who received equivalent dosages based on body surface area. (See Special Populations under Pharmacokinetics.)

Dosage of 5 mcg/m² daily on days 1–7 followed by 15 mcg/m² daily on days 8–28 of cycle 1, then 15 mcg/m² daily on days 1–28 of subsequent cycles, recommended for phase 2 studies.

Geriatric Use

In clinical studies in patients with relapsed or refractory ALL, approximately 13% of patients were ≥65 years of age. Efficacy and safety of the drug was generally similar regardless of patient age, except for increased incidence of neurologic toxicities (e.g., cognitive disorder, encephalopathy, confusion) and serious infections in patients ≥65 years of age.

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment. Clearance affected by moderate renal impairment; however, high interpatient variability was apparent. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute) or in those receiving hemodialysis.

Common Adverse Effects

Pyrexia, infection, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, rash, constipation, diarrhea, tremor.

Drug Interactions

No formal drug interaction studies to date.

Drugs Metabolized by Hepatic Microsomal Enzymes

Transient release of cytokines may result in suppression of CYP isoenzymes and potentially increase serum concentrations of drugs metabolized by CYP isoenzymes. Risk of drug interactions is highest during days 1–9 of cycle 1 and days 1–2 of cycle 2.

Monitor for toxicity and/or changes in serum concentrations in patients receiving CYP substrates, particularly those with a low therapeutic index that require individualized dosing; adjust dosage of the CYP substrate as needed.

Specific Drugs

Blinatumomab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations are dose proportional over the dosage range of 5–90 mcg/m² daily and reached within 1 day in patients receiving blinatumomab by continuous IV infusion.

Distribution

Extent

Not known whether blinatumomab is distributed into milk.

Elimination

Metabolism

Not characterized. Expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination Route

Negligible amounts of the drug are detectable in urine at steady state.

Half-life

2.11 hours.

Special Populations

Approximately twofold difference in mean clearance between patients with moderate renal impairment (Cl_cr 30–59 mL/minute) and those with normal renal function; however, high interpatient variability was apparent and clearance values in patients with renal impairment were within the range observed in patients with normal renal function.

Age, gender, body weight, and body surface area do not have meaningful effects on pharmacokinetics of blinatumomab.

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug and IV solution stabilizer: 2–8°C in original package to protect from light. Do not freeze. May store at room temperature for up to 8 hours.

Reconstituted drug: 23–27°C for up to 4 hours or 2–8°C for up to 24 hours. Protect from light.

Diluted infusion solution: 23–27°C for up to 48 hours (including infusion time) or 2–8°C for up to 8 days. Do not freeze.

Compatibility

Parenteral

Solution Compatibility

Actions

• Single-chain antibody composed of the variable fragments of antibodies to CD3 and CD19 connected by a nonglycosylated, nonimmunogenic linker protein that allows for rotational flexibility and close proximity of malignant CD19⁺ B cells to CD3⁺ T cells.

• Binds specifically to CD3 signaling chain of the T-cell receptor (TCR) complex and antigen CD19 on normal and malignant B lymphocytes.

• Apoptosis of CD19⁺ B cells occurs following activation of endogenous T cells.

• Causes initial redistribution of peripheral T cells, decreased peripheral B-cell counts, and transient release of proinflammatory cytokines (interleukin-2 [IL-2], interleukin-4 [IL-4], interleukin-6 [IL-6], interleukin-10 [IL-10], tumor necrosis factor [TNF; TNF-α], interferon gamma). Incidence and intensity of elevated cytokine levels are greatest during initial 48 hours of first treatment cycle.

Advice to Patients

• Importance of reading the manufacturer's medication guide before beginning treatment and each time blinatumomab is administered.

• Risk of cytokine release syndrome and infusion-related reactions. Importance of immediately reporting signs and symptoms of such reactions (e.g., pyrexia, fatigue, dizziness, headache, nausea, vomiting, chills, hypotension, rash, facial swelling, wheezing).

• Risk of neurologic toxicity. Importance of informing clinician immediately if signs and symptoms of neurologic toxicity (e.g., seizures, speech impairment, loss of consciousness, confusion, loss of balance) occur. Importance of not driving or engaging in hazardous occupations or activities (e.g., operating hazardous machinery) while receiving the drug.

• Risk of infections. Importance of immediately contacting clinician if symptoms suggestive of an infection develop. Importance of keeping the IV injection site clean to reduce the risk of catheter-related infection.

• Risk of tumor lysis syndrome.

• Risk of neutropenia and importance of CBC monitoring.

• Risk of hepatotoxicity and importance of liver function test monitoring.

• Necessity of not adjusting settings on the infusion pump. Inform clinician immediately if a problem with the infusion pump occurs or the pump alarm sounds.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of not breast-feeding during therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

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