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Blinatumomab

Medically reviewed by Drugs.com. Last updated on Apr 27, 2020.

Pronunciation

(blin a TOOM oh mab)

Index Terms

  • AMG103
  • MT103

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]

Brand Names: U.S.

  • Blincyto

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD19/CD3
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

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.

Distribution

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

Excretion

Urine (negligible amounts).

Clearance: Mean systemic clearance: Adults: 3.11 L/hour.

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

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Infants, Children, and Adolescents: If the interruption after an adverse reaction 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 reaction 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 adverse reaction 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 adverse reaction 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 adverse reaction 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 adverse reaction 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 adverse reaction is ≤ Grade 1 (mild), then restart 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 adverse reaction 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 adverse reaction takes more than 14 days to resolve, discontinue permanently.

Grade 4: Consider discontinuing permanently.

Dosing: Adjustment for Toxicity

If the interruption after an adverse reaction 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 reaction is >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 adverse reaction 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 ≥3 days and until ≤ 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 adverse reaction does not recur. If adverse reaction occurred at the 9 mcg daily dose (or 5 mcg/m2/day dose if <45 kg), or if it takes >7 days to resolve, discontinue permanently.

Grade 4: Discontinue blinatumomab permanently.

Seizure: Discontinue blinatumomab permanently if >1 seizure occurs.

Other clinically relevant toxicity:

Grade 3: Interrupt blinatumomab therapy until ≤ grade 1 (mild), then restart 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 adverse reaction does not recur. If adverse reaction takes >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), directing stream toward the side of the vial and gently swirl to avoid excess foaming; do not shake. The 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 >1 blinatumomab vial.

24- or 48-hour infusion: Add 270 mL NS to an empty IV bag; use only polyolefin, non-DEHP PVC, or EVA infusion bags or pump cassettes. Transfer 5.5 mL of IV solution stabilizer to the IV bag (discard vial containing balance of IV solution stabilizer); 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. Discard vial containing balance of reconstituted blinatumomab. 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 (removing air from bag is particularly important for ambulatory infusion pumps). Prime the IV tubing only with the final prepared solution for infusion; 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 EVA infusion bags or pump cassettes. Transfer 2.2 mL of IV solution stabilizer to the IV bag (discard vial containing balance of IV solution stabilizer); 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. Discard vial containing balance of reconstituted blinatumomab. Add NS to the IV bag to a final volume of 110 mL; gently mix (avoid foaming). Attach the IV tubing (use only polyolefin, non-DEHP PVC, or EVA tubing) to the bag; do not use an in-line filter for the 7-day infusion bag. Remove air from the IV bag (removing air from bag is particularly important for ambulatory infusion pumps). Prime the IV tubing only with the final prepared solution for infusion; 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. Do not use an in-line filter for the 7-day infusion bag.

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

Infusion bag contains overfill (to account for tubing priming volume). Discard unused infusion solution after completion of infusion. 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); do not freeze. Protect from light. Intact vials of both drug and stabilizer may be stored for a maximum of 8 hours at 23°C to 27°C (73°F to 81°F) in the original carton to protect from light. Reconstituted solution in the vial 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). If not used immediately, solutions diluted for infusion should be refrigerated. 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. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. 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

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

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. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

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

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. 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. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. 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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. 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

ALERT: U.S. Boxed Warning

Cytokine release syndrome:

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving blinatumomab. Interrupt or discontinue blinatumomab and treat with corticosteroids as recommended.

Neurotoxicity:

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

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:

• 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

Reproductive Considerations

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.

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.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Painful extremities

• Back pain

• Bone pain

• Weight gain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, 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

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting

• Infection

• Confusion

• Loss of balance

• Seizures

• Trouble sleeping

• Trouble speaking

• Trouble hearing

• Trouble swallowing

• Trouble with face movements

• Severe headache

• Severe dizziness

• Passing out

• Vision changes

• Chest pain

• Abnormal heartbeat

• Shortness of breath

• Swelling

• Tremors

• Bruising

• Bleeding

• Severe loss of strength and energy

• Swollen glands

• Trouble with memory

• Severe fatigue

• Flushing

• Dark urine

• Yellow skin or eyes

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.