Blinatumomab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Blincyto: 35 mcg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Blinatumomab is a bispecific T-cell engager (BiTE) which binds to CD19 expressed on B-cells and CD3 expressed on T-cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on B-cells (malignant and benign), thus forming a cytolytic synapse between a cytotoxic T-cell and the cancer target B-cell (Topp 2014). Blinatumomab mediates the production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in lysis of CD19-positive cells.

Pharmacokinetics/Pharmacodynamics

Distribution

Pediatric patients <18 years: 3.14 ± 2.97 L/m²; Adults: 4.35 L

Excretion

Urine (negligible amounts)

Half-Life Elimination

Pediatric patients <18 years: 2.04 ± 1.35 hours; Adults: 2.1 hours

Use: Labeled Indications

Acute lymphoblastic leukemia, relapsed or refractory: Treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children

ALL, minimal residual disease-positive: Treatment of B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥0.1% in adults and children

Contraindications

Known hypersensitivity to blinatumomab or any component of the formulation

Dosage and Administration

Dosing: Adult

Acute lymphoblastic leukemia (B-cell precursor), minimal residual disease (MRD)-positive (≥0.1%): IV: Each induction or consolidation treatment cycle consists of 4 weeks of continuous infusion followed by a 2-week treatment-free interval (allow at least 2 weeks treatment-free between cycles). Therapy involves 1 induction cycle followed by up to 3 additional cycles for consolidation (total of up to 4 cycles). In the clinical study, patients could proceed to transplant at any time after cycle 1 (Gökbuget 2018).

Note: Hospitalization is recommended for the first 3 days of cycle 1, and the first 2 days of cycle 2. Close observation by a health care professional (or hospitalization) is recommended for initiation of all subsequent cycles or for therapy reinitiation (eg, treatment is interrupted for 4 or more hours). Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose.

Premedicate with the IV equivalent to prednisone 100 mg or dexamethasone 16 mg IV one hour prior to the first dose of each cycle.

Patients ≥45 kg (fixed dose): Cycles 1 to 4: 28 mcg daily administered as a continuous infusion on days 1 to 28 of a 6-week treatment cycle (Gökbuget 2018)

Patients <45 kg (dose based on BSA): Cycles 1 to 4: 15 mcg/m²/day (maximum: 28 mcg/day) as a continuous infusion on days 1 to 28 of a 6-week treatment cycle (Gökbuget 2018)

Acute lymphoblastic leukemia (B-cell precursor), relapsed/refractory: IV: Each induction or consolidation treatment cycle consists of 4 weeks of continuous infusion followed by a 2-week treatment-free interval (allow at least 2 weeks treatment-free between cycles). Each continued therapy cycle consists of 4 weeks of continuous infusion followed by an 8-week treatment-free interval. Therapy involves up to 2 induction cycles followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy (total of up to 9 cycles). In the clinical study, if appropriate, patients could proceed to transplant at any time after cycle 1 (Kantarjian 2017).

Note: Hospitalization is recommended for the first 9 days of cycle 1, and the first 2 days of cycle 2. Close observation by a health care professional (or hospitalization) is recommended for initiation of all subsequent cycles or for therapy reinitiation (eg, treatment is interrupted for 4 or more hours). Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose.

Premedicate with dexamethasone 20 mg one hour prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), and when restarting therapy after an interruption of ≥4 hours.

Patients ≥45 kg (fixed dose):

Cycle 1: 9 mcg daily administered as a continuous infusion on days 1 to 7, followed by 28 mcg daily as a continuous infusion on days 8 to 28 of a 6-week treatment cycle (Kantarjian 2017)

Cycles 2 through 5: 28 mcg daily administered as a continuous infusion on days 1 to 28 of a 6-week treatment cycle (Kantarjian 2017)

Cycles 6 through 9: 28 mcg daily administered as a continuous infusion on days 1 to 28 of a 12-week treatment cycle (Kantarjian 2017)

Patients <45 kg (dose based on BSA):

Cycle 1: 5 mcg/m²/day (maximum: 9 mcg/day) administered as a continuous infusion on days 1 to 7, followed by 15 mcg/m²/day (maximum: 28 mcg/day) as a continuous infusion on days 8 to 28 of a 6-week treatment cycle

Cycles 2 through 5: 15 mcg/m²/day (maximum: 28 mcg/day) administered as a continuous infusion on days 1 to 28 of a 6-week treatment cycle

Cycles 6 through 9: 15 mcg/m²/day (maximum: 28 mcg/day) administered as a continuous infusion on days 1 to 28 of a 12-week treatment cycle

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Acute lymphoblastic leukemia (B-cell precursor), MRD-positive (≥0.1%): Children and Adolescents: Note: Use in infants may be directed within certain investigational protocols; refer to specific protocols for additional information.

Note: Hospitalization is recommended for the first 3 days of cycle 1 and the first 2 days of cycle 2. Close observation by a health care professional (or hospitalization) is recommended for initiation of all subsequent cycles or for therapy reinitiation (eg, treatment is interrupted for 4 or more hours). Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose.

Premedicate with dexamethasone 5 mg/m² (maximum dose: 20 mg/dose) 1 hour prior to the first dose of the first cycle, or when restarting therapy after an interruption of ≥4 hours in the first cycle.

Blinatumomab treatment course involves 1 induction cycle followed by up to 3 additional cycles for consolidation (total of up to 4 cycles).

Patient weight <45 kg: BSA-directed dosing:

Induction: Cycle 1: Days 1 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by a 2-week treatment-free interval.

Consolidation:Cycles 2 to 4: Days 1 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by a 2-week treatment-free interval.

Patient weight ≥45 kg: Fixed dosing:

Induction: Cycle 1:Days 1 to 28: IV: 28 mcg daily administered as a continuous infusion followed by a 2-week treatment-free interval.

Consolidation: Cycles 2 to 4: Days 1 to 28: IV: 28 mcg daily administered as a continuous infusion followed by a 2-week treatment-free interval.

Acute lymphoblastic leukemia (B-cell precursor), relapsed/refractory: Infants, Children, and Adolescents:

Note: Hospitalization is recommended for the first 9 days of cycle 1, and the first 2 days of cycle 2. Close observation by a healthcare professional (or hospitalization) is recommended for initiation of all subsequent cycles or for therapy reinitiation (eg, treatment is interrupted for 4 or more hours). Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose.

Premedicate with dexamethasone IV 5 mg/m² (maximum dose: 20 mg/dose) 1 hour prior to the first dose of the first cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting therapy after an interruption of ≥4 hours in the first cycle.

Blinatumomab treatment course involves 2 induction cycles followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy (total of up to 9 cycles).

Patient weight <45 kg: BSA-directed:

Induction:

Cycle 1:

Days 1 to 7: IV: 5 mcg/m²/day (maximum daily dose: 9 mcg/day) administered as a continuous infusion.

Days 8 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by a 2-week treatment-free interval.

Cycle 2: Days 1 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by a 2-week treatment-free interval.

Consolidation: Cycles 3 through 5: Days 1 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by a 2-week treatment-free interval.

Continued therapy: Cycles 6 through 9: Days 1 to 28: IV: 15 mcg/m²/day (maximum daily dose: 28 mcg/day) administered as a continuous infusion followed by 8-week treatment-free interval.

Patient weight ≥45 kg: Fixed dosing:

Induction:

Cycle 1:

Days 1 to 7: IV: 9 mcg daily administered as a continuous infusion.

Days 8 to 28: IV: 28 mcg daily administered as a continuous infusion followed by a 2-week treatment-free interval.

Cycle 2: Days 1 to 28: IV: 28 mcg daily administered as a continuous infusion followed by a 2-week treatment-free interval.

Consolidation: Cycles 3 through 5: Days 1 to 28: IV: 28 mcg daily administered as a continuous infusion followed by a 2-week treatment-free interval.

Continued therapy: Cycles 6 through 9: Days 1 to 28: IV: 28 mcg daily administered as a continuous infusion followed by an 8-week treatment-free interval.

Dosing adjustment for toxicity: Infants, Children, and Adolescents: If the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of the days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle.

Cytokine release syndrome (CRS):

Grade 3: Interrupt blinatumomab therapy, administer dexamethasone according to the following; and upon resolution, resume blinatumomab at the following reduced doses:

Dexamethasone: IV, Oral:

Patient weight <45 kg: 5 mg/m²/dose (maximum dose: 8 mg/dose) every 8 hours for up to 3 days, then taper over 4 days.

Patient weight ≥45 kg: 8 mg/dose every 8 hours for up to 3 days, then taper over 4 days.

Blinatumomab: After resolution, resume therapy at the following reduced doses:

Patient weight <45 kg: 5 mcg/m²/day (maximum daily dose: 9 mcg/day); if after 7 days toxicity does not recur, further increase dose to 15 mcg/m²/day (maximum daily dose: 28 mcg/day).

Patient weight ≥45 kg: 9 mcg/day. If after 7 days toxicity does not recur, further increase dose to 28 mcg/day.

Grade 4: Discontinue blinatumomab permanently, administer dexamethasone according to the following:

Dexamethasone: IV, Oral:

Patient weight <45 kg: 5 mg/m²/dose (maximum dose: 8 mg/dose) every 8 hours for up to 3 days, then taper over 4 days.

Patient weight ≥45 kg: 8 mg/dose every 8 hours for up to 3 days, then taper over 4 days.

Neurologic toxicity:

Grade 3: Interrupt therapy for at least 3 days and until toxicity is ≤ Grade 1 (mild), then resume blinatumomab dosing at 5 mcg/m²/day if <45 kg (maximum daily dose: 9 mcg/day) or 9 mcg/day if ≥45 kg. If after 7 days toxicity does not recur, further increase blinatumomab dose to 15 mcg/m²/day if <45 kg (maximum daily dose: 28 mcg/day) or to 28 mcg/day if ≥45 kg. If toxicity occurred at the 5 mcg/m²/day dose (if <45 kg) or 9 mcg daily dose, or if it takes more than 7 days to resolve, discontinue permanently.

Grade 4: Discontinue permanently.

Seizure: Discontinue permanently if more than 1 seizure occurs.

Other clinically relevant toxicity:

Grade 3: Interrupt therapy until toxicity is ≤ Grade 1 (mild), then resume blinatumomab dosing at 5 mcg/m²/day if <45 kg (maximum daily dose: 9 mcg/day) or 9 mcg/day if ≥45 kg. If after 7 days toxicity does not recur, further increase blinatumomab dose to 15 mcg/m²/day if <45 kg (maximum daily dose: 28 mcg/day) or to 28 mcg/day if ≥45 kg. If toxicity takes more than 14 days to resolve, discontinue permanently.

Grade 4: Discontinue permanently.

Dosing: Adjustment for Toxicity

If the interruption after an adverse event is no longer than 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 longer than 7 days, start a new cycle.

Cytokine release syndrome (CRS):

Grade 3: Interrupt blinatumomab therapy. Administer dexamethasone 8 mg (or 5 mg/m² if <45 kg; maximum: 8 mg) IV or orally every 8 hours for up to 3 days, then taper over 4 days. Upon resolution, resume blinatumomab dosing at 9 mcg daily (or 5 mcg/m²/day if <45 kg). Increase dose to 28 mcg daily (or 15 mcg/m²/day if <45 kg) after 7 days if toxicity does not recur.

Grade 4: Discontinue blinatumomab permanently. Administer dexamethasone 8 mg (or 5 mg/m² if <45 kg; maximum: 8 mg) IV or orally every 8 hours for up to 3 days, then taper over 4 days.

Neurologic toxicity:

Grade 3: Interrupt blinatumomab therapy for at least 3 days and until toxicity is ≤ Grade 1 (mild), then resume dosing at 9 mcg daily (or 5 mcg/m²/day if <45 kg). Increase dose to 28 mcg daily (or 15 mcg/m²/day if <45 kg) after 7 days if toxicity does not recur. If toxicity occurred at the 9 mcg daily dose (or 5 mcg/m²/day dose if <45 kg), or if it takes more than 7 days to resolve, discontinue permanently.

Grade 4: Discontinue blinatumomab permanently.

Seizure: Discontinue blinatumomab permanently if more than 1 seizure occurs.

Other clinically relevant toxicity:

Grade 3: Interrupt blinatumomab therapy until toxicity is ≤ Grade 1 (mild), then resume dosing at 9 mcg daily (or 5 mcg/m²/day if <45 kg). Increase dose to 28 mcg daily (or 15 mcg/m²/day if <45 kg) after 7 days if toxicity does not recur. If toxicity takes more than 14 days to resolve, discontinue permanently.

Grade 4: Consider discontinuing blinatumomab permanently.

Reconstitution

Note: Preparation and administration errors have occurred; follow preparation instructions carefully. Refer to manufacturer labeling for further information.

Reconstitute each vial of lyophilized powder with 3 mL of preservative-free SWFI (do not reconstitute vials with the IV solution stabilizer); direct stream toward the side of the vial and gently swirl to avoid excess foaming. Do not shake; final reconstituted concentration is 12.5 mcg/mL. Reconstituted solution should be clear to slightly opalescent, colorless to slightly yellow; do not use if cloudy or if precipitation occurs. Note: Some doses may require reconstitution of more than 1 vial of lyophilized powder.

24- or 48-hour infusion: Add 270 mL NS to an empty IV bag; use only polyolefin, non-DEHP PVC (non-di-ethylhexylphthalate PVC), or ethyl vinyl acetate (EVA) infusion bags or pump cassettes. Transfer 5.5 mL of IV solution stabilizer to the IV bag; gently mix to avoid foaming. Transfer the appropriate volume of reconstituted blinatumomab solution to the IV bag and gently mix; refer to manufacturer labeling for the specific volume of reconstituted drug to be added. Attach the IV tubing (use only polyolefin, non-DEHP PVC, or EVA tubing) to the bag with a sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter. Remove air from the IV bag. Prime the IV tubing only with the prepared infusion solution; do not prime with NS. If not used immediately, store at 2°C to 8°C (36°F to 46°F) for up to 8 days (infusion must be completed within this time frame).

7-day infusion (not recommended for patients weighing <22 kg): Add 90 mL bacteriostatic NS to an empty IV bag; use only polyolefin, non-DEHP PVC, or ethyl vinyl acetate (EVA) infusion bags or pump cassettes. Transfer 2.2 mL of IV solution stabilizer to the IV bag; gently mix to avoid foaming. Transfer the appropriate volume of reconstituted blinatumomab solution to the IV bag and gently mix; refer to manufacturer labeling for the specific volume of reconstituted drug to be added. Add NS to the IV bag to a final volume of 110 mL (resulting in 0.74% benzyl alcohol); gently mix (avoid foaming). Attach the IV tubing (use only polyolefin, non-DEHP PVC, or EVA tubing) to the bag; an in-line filter is not required for the 7-day infusion bag. Remove air from the IV bag. Prime the IV tubing only with the prepared infusion solution; do not prime with NS. If not used immediately, store at 2°C to 8°C (36°F to 46°F) for up to 14 days (infusion must be completed within this time frame).

Administration

Note: Preparation and administration errors have occurred; carefully follow administration instructions.

IV:

24- or 48-hour infusion: Administer 240 mL as a continuous IV infusion at a constant flow rate of 10 mL/hour for 24 hours or 5 mL/hour for 48 hours (depending on dose, duration, and/or concentration) through a dedicated lumen. Use a programmable, lockable, non-elastomeric infusion pump with an alarm; IV tubing should include a sterile, nonpyrogenic, low protein-binding, 0.2 micron in-line filter.

7-day infusion (not recommended in patients weighing <22 kg): Administer 100 mL as a continuous IV infusion at a constant flow rate of 0.6 mL/hour for 7 days through a dedicated lumen. Use a programmable, lockable, non-elastomeric infusion pump with an alarm; an in-line filter is not required for the 7-day infusion bag.

Only use polyolefin, non-DEHP PVC (non-di-ethylhexylphthalate PVC), or ethyl vinyl acetate (EVA) infusion bags, pump cassettes, and IV tubing. IV tubing should be primed with prepared infusion solution, not NS. Premedication is required prior to some doses (see Dosing: Adult for further details).

Infusion bag contains overfill (to account for tubing priming volume). Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in excess dosage and complications. Do not infuse other medications through the same line.

Storage

Store intact vials (drug and solution stabilizer) in the original package at 2°C to 8°C (36°F to 46°F); protect from light. Do not freeze. Intact vials of both drug and stabilizer may be stored for up to 8 hours at room temperature. Reconstituted solution is stable for up to 4 hours at 23°C to 27°C (73°F to 81°F) or up to 24 hours at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion (preservative free) are stable in NS for up to 48 hours at 23°C to 27°C (73°F to 81°F) or up to 8 days at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion (with preservative) are stable in NS for up to 7 days at 23°C to 27°C (73°F to 81°F) or up to 14 days at 2°C to 8°C (36°F to 46°F). Infusion should be completed within these time frames; if IV bag of solution for infusion is not administered within the time frames and temperatures indicated, discard; do not refrigerate again.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Busulfan: Blinatumomab may increase the serum concentration of Busulfan. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Edema (18%), hypotension (≤14%), cardiac arrhythmia (12% to 14%)

Central nervous system: Neurotoxicity (65%), headache (23% to 39%), chills (≤28%), insomnia (≤18%), aphasia (≤12%)

Dermatologic: Skin rash (12% to 16%)

Hematologic & oncologic: Decreased absolute lymphocyte count (grades 3 or 4: 80%), neutropenia (15% to 31%; ≥ grade 3: 15% to 28%), anemia (≤25%; ≥ grade 3: 19%), thrombocytopenia (10% to 21%; ≥ grade 3: 6% to 18%), decreased serum immunoglobulins (≤18%; may include IgA, IgG, IgM), leukopenia (8% to 14%; ≤ grade 3: 7% to 9%)

Hepatic: Increased serum transaminases (9% to 15%), increased serum ALT (grades 3/4: 11%)

Hypersensitivity: Cytokine release syndrome (7% to 15%)

Infection: Infection (28% to 39%), bacteremia (≤25%), opportunistic infection (≤25%), sepsis (≤25%), serious infection (≤25%), bacterial infection (≤14%), viral infection (≤11%)

Local: Catheter infection (≤25%)

Neuromuscular & skeletal: Tremor (≤31%; may include essential tremor, intentional tremor, resting tremor), back pain (≤12%)

Respiratory: Pneumonia (≤25%), cough (13%)

Miscellaneous: Fever (55% to 91%), infusion-related reaction (30% to 77%)

1% to 10%:

Cardiovascular: Septic shock (≥2%)

Central nervous system: Brain disease (≤10%), dizziness (≤10%), seizure (≥2%)

Endocrine & metabolic: Weight gain (≤10%)

Hematologic & oncologic: Febrile neutropenia (≥2%)

Hepatic: Increased serum AST (grades 3/4: 8%), increased serum bilirubin (grades 3/4: 5%)

Immunologic: Antibody development (<2%; most were neutralizing)

Infection: Fungal infection (≤10%), staphylococcal infection (≥2%)

Frequency not defined:

Cardiovascular: Capillary leak syndrome, chest discomfort, chest pain, circulatory shock, flushing, hypertension, hypertensive crisis, peripheral edema

Central nervous system: Altered mental status, cognitive dysfunction, confusion, cranial nerve dysfunction (includes facial nerve disorder, trigeminal nerve disorder), depression, disorientation, disturbance in attention, disturbed coordination, drowsiness, equilibrium disturbance, facial paresis, hyperthermia, hypoesthesia, impaired consciousness, intention tremor, lethargy, memory impairment, noncardiac chest pain, pain, sixth nerve palsy, speech disturbance, stupor, suicidal ideation, trigeminal neuralgia

Dermatologic: Allergic dermatitis, erythema multiforme, urticaria

Endocrine & metabolic: Hot flash, hypovolemic shock

Hematologic & oncologic: Hematologic abnormality (hematophagic histiocytosis), hypogammaglobulinemia, leukocytosis, lymphadenopathy, tumor lysis syndrome

Hepatic: Increased serum alkaline phosphatase

Hypersensitivity: Anaphylaxis, angioedema, fixed drug eruption, hypersensitivity reaction

Neuromuscular & skeletal: Limb pain, musculoskeletal chest pain, ostealgia

Respiratory: Acute asthma, acute respiratory tract failure, bronchospasm, dyspnea, dyspnea on exertion, productive cough, respiratory distress, tachypnea, wheezing

<1%, postmarketing, and/or case reports: Leukoencephalopathy, pancreatitis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia and neutropenic fever, including life-threatening episodes, have been reported. Monitor blood counts throughout therapy; may require therapy interruption if prolonged neutropenia occurs. Anemia and thrombocytopenia may also occur.
• Cytokine release syndrome: [US Boxed Warning]: Cytokine release syndrome (CRS), which may be life-threatening or fatal, has occurred. Interrupt or discontinue therapy and treat with corticosteroids as recommended. CRS manifestations may include pyrexia, headache, nausea, weakness, hypotension, increased transaminases, elevated total bilirubin, and disseminated intravascular coagulation (DIC). Symptoms of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) may overlap with CRS symptoms. Monitor closely for signs/symptoms of these conditions, and advise patients to reports signs/symptoms suggestive of CRS; may require therapy interruption or discontinuation. Administer corticosteroids for severe or life-threatening CRS. The median time to onset and resolution of CRS was 2 days (following the start of infusion) and 5 days (among cases that resolved), respectively. In one study, patients with a high tumor burden (≥50% leukemic blasts or >15,000/mm³ peripheral blood leukemic blast counts), or elevated lactate dehydrogenase were pre-treated with dexamethasone (10 to 24 mg/m²/day for up to 5 days and concluding 3 days prior to initiating blinatumomab) to reduce the incidence of severe CRS (Topp 2015). Tocilizumab may be considered in the management of severe or life-threatening CRS associated with bi-specific T-cell engaging (BiTE) therapy (Lee 2014; Maude 2014).
• Hepatotoxicity: Transient increases in liver enzymes (associated both with and without CRS) may occur during therapy. In patients with acute lymphoblastic leukemia (ALL), the median time to enzyme elevation was 3 to 19 days; grade 3 or higher elevations were observed in a small percentage of patients. Monitor ALT, AST, GGT, and total bilirubin at baseline and during treatment. Interrupt therapy if transaminases are >5 times ULN or if total bilirubin is >3 times ULN.
• Infection: Serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-related infections have been reported in approximately one-fourth of patients with ALL in clinical trials (may be life-threatening or fatal). Consider prophylactic antibiotics if appropriate, and monitor closely for signs/symptoms of infection. Treat promptly if infection occurs.
• Leukoencephalopathy: Leukoencephalopathy (as seen on MRI) has been reported, particularly in those patients who received prior treatment with cranial irradiation and antileukemia chemotherapy (eg, high-dose methotrexate, intrathecal cytarabine).
• Neurotoxicity: [US Boxed Warning]: Neurological toxicities, which may be severe, life-threatening, or fatal, have occurred. Interrupt or discontinue therapy as recommended. Neurotoxicity has occurred in almost two-thirds of patients with ALL in clinical trials. The median time to onset was within the first 2 weeks of therapy. Common neurological symptoms include headache and tremor (symptoms may differ in children <2 years of age, and elderly patients have a higher incidence of neurotoxicity). Grade 3 or higher neurotoxicity (eg, encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders) has also been observed; other manifestations have included cranial nerve disorders. Neurotoxicity may be managed with dexamethasone (Topp 2015). Patients are at risk for loss of consciousness due to neurologic events while taking blinatumomab; advise patients to avoid driving, participating in hazardous occupations, or operating heavy or dangerous machinery during treatment. Patients with a history of (or current) clinically relevant CNS pathology were excluded from clinical trials. Monitor patients for signs/symptoms of neurotoxicity, and advise patients to reports signs/symptoms suggestive of neurologic toxicity; may require therapy interruption or discontinuation. The majority of symptoms resolved after interrupting therapy.
• Pancreatitis: Fatal cases of pancreatitis in patients receiving blinatumomab plus dexamethasone have been reported in the postmarketing setting. Monitor for signs/symptoms of pancreatitis; may require therapy interruption or discontinuation.
• Tumor lysis syndrome: Life-threatening or fatal tumor lysis syndrome (TLS) has been observed. Administer measures to prevent TLS (eg, pretreatment nontoxic cytoreduction and hydration during treatment). Monitor for signs/symptoms of TLS (eg, acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia); may require treatment interruption or discontinuation.

Concomitant drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Vaccines: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to blinatumomab initiation, during treatment, and until immune system recovery following the last cycle of therapy.

Special populations:

• Elderly: Elderly patients experienced an increased rate of neurotoxicity (including cognitive disorder), encephalopathy, confusion, and serious infections as compared to patients <65 years of age.
• Pediatric: Pediatric patients experienced an increased rate of anemia, leukopenia, thrombocytopenia, pyrexia, infusion reaction, weight gain, and hypertension as compared to adult patients. While the incidence of neurologic toxicities in patients <2 years of age did not differ from other age groups, the manifestations were different; reported toxicities were agitation, headache, insomnia, somnolence, and irritability. Infants experienced an increased incidence of hypokalemia compared to adults and to older pediatric patients.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Diluent may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Due to the addition of bacteriostatic saline, the 7-day infusion bags of blinatumomab contain benzyl alcohol and are not recommended for use in patients weighing <22 kg.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Safety issue: Preparation and administration errors have occurred. Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose and complications. IV bag contains overfill and volume will be more than the volume administered to the patient to account for IV line priming and to ensure that the full dose is administered. Follow preparation and administration instructions carefully. Refer to manufacturer labeling for further information.

Monitoring Parameters

CBC with differential, liver function tests (ALT, AST, GGT, and total bilirubin) at baseline and throughout therapy; monitor for signs/symptoms of cytokine release syndrome, infusion reactions, neurotoxicity, infection, pancreatitis, and tumor lysis syndrome

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, blinatumomab may cause fetal harm when administered to a pregnant female. Newborns exposed in utero may develop B-cell lymphocytopenia; monitor B-lymphocytes prior to administering live virus vaccines.

Verify pregnancy status of females of reproductive potential prior to initiating treatment; effective contraception should be used during treatment and for at least 48 hours after the last blinatumomab dose.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Painful extremities
• Back pain
• Bone pain
• Trouble sleeping
• Weight gain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Cytokine release syndrome like chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, swelling in your throat, trouble breathing, nausea, vomiting, or wheezing.
• Confusion
• Loss of balance
• Seizures
• Trouble speaking
• Infection
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Chest pain
• Shortness of breath
• Edema
• Tremors
• Bruising
• Bleeding
• Severe loss of strength and energy
• Swollen glands
• Trouble with memory
• Severe fatigue
• Flushing
• Yellow skin
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.