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Blinatumomab

Pronunciation

(blin a TOOM oh mab)

Index Terms

  • 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 0 to 17 years: 3.14 ± 2.97 L/m2; Adults: 4.35 L

Excretion

Urine (negligible amounts)

Half-Life Elimination

Pediatric patients 0 to 17 years: 2.04 ± 1.35 hours; Adults: 2.1 hours

Use: Labeled Indications

Acute lymphoblastic leukemia: Treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

Contraindications

Known hypersensitivity to blinatumomab or any component of the formulation

Dosing: Adult

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

Acute lymphoblastic leukemia (B-cell precursor), relapsed/refractory: IV: Each induction and 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).

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

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

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

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

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 5 mg/m2 (maximum: 20 mg) one 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.

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 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).

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

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

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

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: Renal Impairment

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, a pharmacokinetic analysis showed that clearance values in patients with CrCl 30 to 59 mL/minute were similar to the range observed in patients with normal renal function.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment: Interrupt therapy if transaminases are >5 times ULN or if bilirubin is >3 times ULN.

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 therapy until resolved, 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.

Grade 4: Discontinue permanently

Neurologic toxicity:

Grade 3: Interrupt 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 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 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 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. For adults, premedicate with dexamethasone 20 mg one hour prior to the first dose of each cycle, prior to a step dose (such as cycle 1 day 8), or when restarting therapy after an interruption of ≥4 hours. For pediatric patients, premedicate with dexamethasone 5 mg/m2 (maximum: 20 mg) one 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.

Infuse 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

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

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. Avoid combination

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. 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

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. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Edema (18%), cardiac arrhythmia (14%)

Central nervous system: Headache (23%)

Dermatologic: Skin rash (12%)

Hematologic & oncologic: Decreased absolute lymphocyte count (grades 3 or 4: 80%), neutropenia (31%; ≥ grade 3: 28%), anemia (25%; ≥ grade 3: 19%), thrombocytopenia (21%; ≥ grade 3: 18%)

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

Hypersensitivity: Cytokine release syndrome (14%)

Infection: Infection (28%), serious infection (25%), bacterial infection (14%), viral infection (11%)

Neuromuscular & skeletal: Tremor (≥10%; includes essential tremor, intentional tremor, resting tremor)

Miscellaneous: Fever (55%), infusion related reaction (30%)

1% to 10%:

Hematologic & oncologic: Leukopenia (8%; ≥ grade 3: 7%)

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

Infection: Fungal infection (10%)

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

Frequency not defined:

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

Central nervous system: Altered mental status, aphasia, ataxia, brain disease, chills, cognitive dysfunction, confusion, depression, disorientation, disturbance in attention, dizziness, drowsiness, equilibrium disturbance, hyperthermia, hypoesthesia, impaired consciousness, insomnia, lethargy, leukoencephalopathy, memory impairment, noncardiac chest pain, pain, seizure (includes atonic seizure), sepsis, speech disturbance, stupor, suicidal ideation

Dermatologic: Allergic dermatitis, erythema multiforme, urticaria

Endocrine & metabolic: Hot flash, hypovolemic shock, weight gain

Hematologic & oncologic: Decreased serum immunoglobulins (including IgA, IgG, IgM), febrile neutropenia, hypogammaglobulinemia, leukocytosis, lymphadenopathy, tumor lysis syndrome

Hepatic: Increased serum alkaline phosphatase

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

Neuromuscular & skeletal: Back pain, limb pain, musculoskeletal chest pain, ostealgia

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

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 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 as recommended. Infusion reactions have also occurred, and may be difficult to distinguish from CRS. CRS symptoms may include pyrexia, headache, nausea, weakness, hypotension, increased transaminases, and elevated total bilirubin. In some patients, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) have been reported in the setting of CRS. Monitor closely for signs/symptoms of these conditions; may require therapy interruption or discontinuation. CRS which was life-threatening or fatal occurred rarely. The highest cytokine elevation was observed in the first 2 days following the start of infusion. In 1 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).

• Hepatotoxicity: Transient increases in liver enzymes (associated both with and without CRS) may occur during therapy. In patients with 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 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, 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. 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; 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.

• Pediatric: Pediatric patients experienced an increased rate of anemia, thrombocytopenia, vomiting, pyrexia, 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.

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 Considerations

Animal reproductions studies have not been conducted. Based on the mechanism of action, blinatumomab may cause fetal harm when administered to a pregnant woman. Newborns exposed in utero may develop B-cell lymphocytopenia; monitor B-lymphocytes prior to administering live virus vaccines. Verify pregnancy status of women of reproductive potential prior to initiating treatment; effective contraception should be used during treatment and for at least 48 hours after the last dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience painful extremities, back pain, bone pain, insomnia, or weight gain. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of cytokine release syndrome (chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, angioedema, difficulty breathing, nausea, vomiting, or wheezing), confusion, loss of balance, seizures, difficulty speaking, signs of infection, signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe headache, severe dizziness, passing out, vision changes, angina, shortness of breath, edema, tremors, bruising, bleeding, severe loss of strength and energy, swollen glands, memory impairment, severe fatigue, flushing, jaundice, or signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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