Drug Safety-related Labeling Changes (SrLC)

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BLINCYTO (BLA-125557)

(BLINATUMOMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/21/2025 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cytokine Release Syndrome

Additions and/or revisions underlined:

. . .

The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). Evaluation for HLH/MAS should be considered when CRS is atypical or prolonged, or when features of macrophage activation are present.

. . .

04/29/2025 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Additions and/or revisions underlined:

…

There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical studies. Patients with Down Syndrome may have a higher risk of seizures with BLINCYTO therapy; consider seizure prophylaxis prior to initiation of BLINCYTO for these patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

People with Down Syndrome may have a higher risk of seizures with BLINCYTO treatment and may be given anti-seizure medicine before starting BLINCYTO treatment.

…

12/17/2024 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Additions and/or revisions underlined:

…

Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, including ICANS. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Management of neurologic toxicity may require interruption or discontinuation of BLINCYTO as recommended and/or treatment with corticosteroids [see Dosage and Administration (2.4)]. 

5.12 Benzyl Alcohol Toxicity in Neonates

Additions and/or revisions underlined:

…

Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Use in Specific Populations (8.4)].

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

Use the preservative-free formulations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load ofbenzyl alcohol from all sources including BLINCYTO (with preservative). The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Warnings and Precautions (5.12)].

Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance. Monitor these patients during use of BLINCYTO (with preservative) for new or worsening metabolic acidosis.

06/14/2024 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cytokine Release Syndrome

Additions and revisions underlined:

Using all of these terms to define CRS in clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL, in 7% of patients with MRD-positive ALL, and in 16% of patients receiving BLINCYTO cycles in the consolidation phase of therapy [see Adverse Reactions (6.1)].

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Newly added information:

Patients with Down Syndrome over the age of 10 years may have a higher risk of seizures with BLINCYTO therapy.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and efficacy of BLINCYTO in pediatric patients less than 1 month of age have not been established for any indication [see Indications and Usage (1)].

The safety and efficacy of BLINCYTO for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% have been established in pediatric patients one month and older.

The safety and efficacy of BLINCYTO have been established in pediatric patients one month and older with relapsed or refractory B-cell precursor ALL.

B-cell Precursor ALL in the Consolidation Phase

The safety and efficacy of BLINCYTO for the treatment of Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients one month and older. Use of BLINCYTO for this indication is supported by extrapolation from a randomized controlled study in adults (Study E1910, NCT02003222) and evidence from two randomized, controlled studies in pediatric patients (Study 20120215 and Study AALL1331) [see Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].

8.5 Geriatric Use

Newly added information:

There were 158 (7%) patients 65 years and older in clinical studies of BLINCYTO for patients with MRD positive, CD19 positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19 positive B-cell precursor ALL, and CD19 positive, Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase. Of the total number of BLINCYTO-treated patients in these studies, 123 (8%) were 65 years of age and older and 21 (1%) were 75 years of age or older.

02/08/2024 (SUPPL-29)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

• Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

• Neurological toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.3), Warnings and Precautions (5.2)].

5 Warnings and Precautions

 

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Subsection title revised

Additions and/or revisions underlined:

BLINCYTO can cause serious or life-threatening neurologic toxicity, including ICANS [see Adverse Reactions 6.1].

The incidence of neurologic toxicities in clinical trials was approximately 65% [see Adverse Reactions (6.1)]. Among patients that experienced a neurologic toxicity, the median time to the first event was within the first 2 weeks of BLINCYTO treatment. The most common (greater than or equal to 10%) manifestations of neurological toxicity were headache, and tremor; the neurological toxicity profile varied by age group [see Use in Specific Populations (8.4, 8.5)]. Grade 3 or higher neurological toxicities following initiation of BLINCYTO administration occurred in approximately 13% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. The majority of neurologic toxicities resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.

The incidence of signs and symptoms consistent with ICANS in clinical trials was 7.5%. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical studies.

Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, including ICANS. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.3)].

5.6 Effects on Ability to Drive and Use Machines

Additions and/or revisions underlined:

Due to the potential for neurologic events, including seizures and ICANS, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

6 Adverse Reactions

Additions and/or revisions underlined:

…

• Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2)]

…

6.1 Clinical Trials Experience

Addition of “May represent ICANS” to footnote section of table 8 and table 9; please refer to label for complete information

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Advise patients of the risk of neurological toxicities, including ICANS, and to contact their healthcare professional for signs and symptoms associated with this event (including convulsions, speech disorders, and confusion) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

…

Driving and Engaging in Hazardous Occupations

Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events, including seizures and ICANS [see Warnings and Precautions (5.6)].

06/20/2023 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Benzyl Alcohol Toxicity in Neonates

Subsection title revised

Newly added information:

Serious adverse reactions, including fatal reactions and the “gasping syndrome,” have been reported in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol [see Use in Specific Populations (8.4)].

Use the preservative-free preparations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway.

Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL [see Use in Specific Populations (8.4)].

5.13 Embryo-Fetal Toxicity

Newly added section

Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and revisions underlined:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BLINCYTO in patients with MRD-positive B cell precursor ALL (n = 137) and Philadelphia chromosome-negative relapsed or refractory B cell precursor ALL (n = 267) was evaluated in three clinical studies. The most common adverse reactions (? 20%) in this pooled population were pyrexia, infusion-related reactions, infections (pathogen unspecified), headache, neutropenia, anemia, and thrombocytopenia.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

Minimal Residual Disease (MRD)-Positive B-cell Precursor ALL

The safety and efficacy of BLINCYTO for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% have been established in pediatric patients. Use of BLINCYTO is supported by evidence from two randomized, controlled trials (Study AALL1331 NCT02101853 and Study 20120215 NCT02393859) in pediatric subjects with first relapsed B-cell precursor ALL. Both studies included pediatric patients with MRD-positive B-cell precursor ALL. The studies included pediatric patients treated with BLINCYTO in the following age groups: 6 infants (1 month up to less than 2 years), 165 children (2 years up to less than 12 years), and 70 adolescents (12 years to less than 17 years). In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with MRD-positive ALL [see Adverse Reactions (6.1)], and no differences in safety were observed between the different pediatric age subgroups.

Relapsed or Refractory B-cell Precursor ALL

The safety and efficacy of BLINCYTO have been established in pediatric patients with relapsed or refractory B-cell precursor ALL. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups [see Clinical Studies (14.2)].

In general, the adverse reactions in BLINCYTO-treated pediatric patients with relapsed or refractory ALL were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL [see Adverse Reactions (6.1)]. Adverse reactions that were observed more frequently (? 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).

In pediatric patients less than 2 years old (infants) with relapsed or refractory ALL, the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).

Benzyl Alcohol Toxicity in Neonates

Serious and fatal adverse reactions, including “gasping syndrome,” can occur in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) treated with benzyl alcohol-preserved drugs intravenously. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (blood concentration of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known [see Warnings and Precautions (5.12)].

Use the preservative-free formulations of Blincyto where possible in neonates. When prescribing BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative). The BLINCYTO 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL [see Warnings and Precautions (5.12)].

Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance. Monitor these patients during use of Blincyto (with preservative) for new or worsening metabolic acidosis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

Newly added information:

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions (5.13) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Warnings and Precautions (5.13) and Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.2)].

Medication Guide

Additions and revisions underlined:

• Neurologic problems. Symptoms of neurologic problems may include:

  • seizures                                                                 o loss of balance

  • difficulty in speaking or slurred speech                     o headache

  • loss of consciousness                                             o difficulty with facial movements, hearing, vision, or

  • trouble sleeping swallowing

  • confusion and disorientation                                     o tremors

. . .

What is BLINCYTO?

BLINCYTO is a prescription medicine used to treat adults and children with:

• B-cell precursor acute lymphoblastic leukemia (ALL) in remission when only a small number of cancer cells remain in the body (minimal residual disease)

. . .

What are the possible side effects of BLINCYTO? BLINCYTO may cause serious side effects, including:

See “What is the most important information I should know about BLINCYTO?”

• Infections. BLINCYTO may cause life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop any signs or symptoms of an infection.

• Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can be life-threatening and may lead to death. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with BLINCYTO, including:

  • nausea and vomiting

  • dark or cloudy urine

  • confusion

  • reduced amount of urine

  • shortness of breath

  • unusual tiredness

  • irregular heartbeat

  • muscle cramps

02/18/2022 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 10. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-related Maximal Grade 3-4* in First Cycle of Therapy

Relapsed or Refractory B-cell Precursor ALL

Newly added to ‘Nervous system disorders’:

Paresthesia

03/11/2021 (SUPPL-19)

5 Warnings and Precautions

5.1 Cytokine Release Syndrome

Additions and/or revisions underlined:

. . .

The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). Evaluation for HLH/MAS should be considered when CRS is atypical or prolonged, or when features of macrophage activation are present.

. . .

03/20/2020 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

8 Use in Specific Populations

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from BLINCYTO, including

B-cell lymphocytopenia, advise patients not to breastfeed during treatment with BLINCYTO and for at least 48 hours after the last dose.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment.

Contraception

Females

BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for at least 48 hours after the last dose.

04/18/2019 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cytokine Release Syndrome

Additions and/or revisions underlined:

… The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Manifestations of CRS include …

… Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Addition of the following statement:

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

11/30/2017 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neurological Toxicities

(Additions and/or revisions are underlined)

…Manifestations of neurological toxicity included cranial nerve disorders. The majority of neurologic events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Relapsed or Refractory B-cell Precursor ALL

Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were:

…

Nervous system disorders: tremor…encephalopathy and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about BLINCYTO?

…

BLINCYTO may cause serious side effects that can be severe, life-threatening, or lead to death, including:

• Neurologic problems. Symptoms of neurologic problems may include:

  • difficulty with facial movements, hearing, vision, or swallowing

How will I receive BLINCYTO?

…

• Your healthcare provider may prescribe continued therapy.

07/11/2017 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cytokine Release Syndrome

(Additions and/or revisions are underlined)

… In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) have been reported in the setting of CRS.

…

5.2 Neurological Toxicities

(Additions and/or revisions are underlined)

In patients with ALL receiving BLINCYTO in clinical studies, neurological toxicities have occurred in approximately 65% of patients. Among patients that experienced a neurologic event, the median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved.

5.3 Infections

(Additions and/or revisions are underlined)

In patients with ALL receiving BLINCYTO in clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal…

5.7 Elevated Liver Enzymes

(Additions and/or revisions are underlined)

… In patients with ALL receiving BLINCYTO in clinical studies, the median time to onset of elevated liver enzymes was 3 days.

The majority of these transient elevations in liver enzymes were observed in the setting of CRS. For the events that were observed outside the setting of CRS, the median time to onset was 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Philadelphia Chromosome-negative Relapsed or Refractory B-cell Precursor ALL

The safety data described below reflect exposure to BLINCYTO in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other.

The most common adverse reactions (greater than or equal to 20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia.  Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (greater than or equal to 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction.  Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections.

The adverse reactions occurring at a greater than or equal to 10% incidence for any grade or greater than or equal to 5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 7.

Table 7. Adverse Reactions Occurring at greater than or equal to 10% Incidence for Any Grade or greater than or equal to 5% Incidence for Grade 3 or Higher in BLINCYTO-treated Patients in First Cycle of Therapy (Table has been revised; please refer to label)

 

Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 8.

Table 8. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-related Maximal Grade 3-4* in First Cycle of Therapy (Table has been revised; please refer to label)

 

Relapsed or Refractory B-cell Precursor ALL

Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and leukocytosis (includes leukocytosis and white blood cell count increased)

General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome

Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia) Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria) Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose)

Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia

Metabolism and nutrition disorders: tumor lysis syndrome

Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity

Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure and atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, and encephalopathy

Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide)

Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough

Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome

6.3 Immunogenicity

(Additions and/or revisions are underlined)

…

In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO.

…

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL. Adverse reactions that were observed more frequently (greater than or equal to 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).

… Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the total number of patients with relapsed or refractory ALL in clinical studies of BLINCYTO, treated at the recommended dose and schedule, approximately 12% were 65 and over, while 3% were 75 and older…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about BLINCYTO?

BLINCYTO may cause serious side effects that can be severe, life-threatening, or lead to death, including:

• Neurologic problems. Symptoms of neurologic problems may include:
• Seizures
• confusion and disorientation
• difficulty in speaking or slurred speech
• loss of balance
• loss of consciousness
• trouble sleeping
• headache

What is BLINCYTO?

BLINCYTO is a prescription medicine used to treat a certain type of acute lymphoblastic leukemia (ALL) in adults and children…

How will I receive BLINCYTO?

• Your healthcare provider will decide the number of treatment cycles of BLINCYTO.
• You will receive BLINCYTO by continuous IV infusion for 4 weeks (28 days), followed by a 2 week (14 days) break during which you will not receive BLINCYTO. This is 1 treatment cycle (42 days). You may receive up to 5 treatment cycles.
• Your healthcare provider may prescribe additional maintenance therapy.
• You will receive BLINCYTO by continuous IV infusion for 4 weeks (28 days), followed by an 8 week (56 days) break during which you will not receive BLINCYTO. You may receive up to 4 treatment cycles of maintenance therapy.

What are the possible side effects of BLINCYTO?

The most common side effects of BLINCYTO include:

• Infections
• Fever
• Headache
• low red blood cell count (anemia)
• low platelet count (thrombocytopenia)
• reactions related to infusion of the medicine such as face swelling, low blood pressure, and high blood pressure (infusion-related reactions)

05/03/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative

(new subsection added)

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including BLINCYTO (with preservative). The “gasping syndrome” is characterized by central nervous syndrome depression, metabolic acidosis, and gasping respirations.

When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) (contains 7.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing less than 22 kg.

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

…

Benzyl Alcohol Toxicity in Pediatric Patients

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing BLINCYTO (with preservative) in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) (contains 7.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion contain benzyl alcohol and are not recommended for use in patients weighing less than 22 kg. Prepare BLINCYTO solution for infusion with preservative-free saline (24- or 48-hour bags) for use in patients weighing less than 22 kg.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(addition underlined)

…

General information about safe and effective use of BLINCYTO

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BLINCYTO for a condition for which it was not prescribed. Do not give BLINCYTO to other people even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BLINCYTO that is written for health professionals.

08/30/2016 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Elevated Liver Enzymes (revised)

• Treatment with BLINCYTO was associated with transient elevations in liver enzymes. In clinical trials, the median time to onset of elevated liver enzymes was 3 days.

• In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.

• Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal.

Neurological Toxicities

• In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 64% of patients. The median time to onset of any neurological toxicity was 4 days. The most common (? 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness; the neurological toxicity profile varied by age group. Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 17% of patients and included encephalopathy…
• There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical trials.

6 Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• The safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 282 patients (212 adult and 70 pediatric patients) with relapsed or refractory ALL were treated with a recommended dose and schedule. All patients received at least one dose of BLINCYTO. The most common adverse reactions (greater than or equal to 20%) in the safety population were pyrexia, headache, nausea, edema, hypokalemia, anemia, febrile neutropenia, neutropenia, thrombocytopenia, and abdominal pain. For some adverse reactions, there were differences in incidence rates by age subgroup.

• The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. In general, the adverse reactions in the BLINCYTO-treated patients less than 45 kg were similar in type to those seen in patients greater than or equal to 45 kg.

Patients Greater Than or Equal to 45 kg

• The median age of patients greater than or equal to 45 kg was 34 years (range: 11 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American.

• Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (? 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, device-related infection, neutropenia, tremor, overdose, encephalopathy, infection, confusion, and headache. Adverse reactions of grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 16% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 12% of patients. The majority of the fatal events were infections. No fatal adverse events occurred on treatment among patients in remission.

Patients Less Than 45 kg

• The median age of patients less than 45 kg was 6 years (range: 7 months to 64 years), 68% were male, and 77% were White.

• Serious adverse reactions were reported in 51% patients. The most common serious adverse reactions (? 2%) included pyrexia, febrile neutropenia, cytokine release syndrome, convulsion, device-related infection, hypoxia, sepsis, and overdose. Adverse reactions of Grade 3 or higher were reported in 88% of patients. Discontinuation of therapy due to adverse reactions occurred in 5% of patients treated with BLINCYTO. Adverse reactions that led to discontinuation of treatment were CRS and fungal infection.

• Three patients experienced a fatal adverse event within 30 days of the last dose of BLINCYTO (2 infection and 1 multi-organ failure after undergoing subsequent HSCT).

• The adverse reactions with greater than or equal to  10% incidence for any grade or greater than or equal to 5% incidence for Grade 3 or higher are summarized in Table 6.

Table 6. Adverse Reactions With greater than or equal to 10% Incidence for Any Grade or greater than or equal to 5% Incidence for Grade 3 or Higher

• Updated; please refer to label.

Following Table 6, the following was added:

• For patients weighing greater than or equal to 45 kg and patients less than 45 kg, additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 6 were, in each weight cohort respectively: leukocytosis (2%, 4%), lymphopenia (1%, 2%), increased gamma-glutamyl-transferase (6%, 2%), tumor lysis syndrome (4%, 0%), hypoalbuminemia (4%, 7%), encephalopathy (5%, 2%), paresthesia (5%, 2%), aphasia (4%, 0%), convulsion (2%, 4%), memory impairment (2%, 0%), cognitive disorder (1%, 0%), speech disorder (< 1%, 0%), confusional state (7%, 0%), and disorientation (3%, 0%), respectively.

• Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%).

• Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 are shown in Table 7.

• Table 7. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-Related Maximal Grade 3-41

  • Added; please refer to label.

8 Use in Specific Populations

Females and Males of Reproductive Potential (PLLR Conversion)

• Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

• Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment.

Contraception

Females

• Advise females of reproductive potential to use effective contraception during treatment and for at least 48 hours after the last dose of BLINCYTO.

Geriatric Use

• Of the total number of patients with relapsed or refractory ALL in clinical studies of BLINCYTO, treated at the recommended dose and schedule, approximately 10% were 65 and over, while 1% were 75 and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections.

Lactation (PLLR Conversion)

Risk Summary

There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during and for at least 48 hours after treatment with BLINCYTO.

Pediatric Use (revised)

• The safety and efficacy of BLINCYTO have been established in pediatric patients. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups.

• In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients. Adverse reactions that were observed more frequently (? 10%) in the pediatric population compared to the adult population were anemia (41% vs 18%), thrombocytopenia (21% vs.11%), vomiting (24% vs. 13%), pyrexia (80% vs. 62%), and hypertension (26% vs. 8%). In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (23%).

• The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on BSA-based regimens.

Pregnancy (PLLR Conversion)

Risk Summary

• Based on its mechanism of action, BLINCYTO may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman. There are no data on the use of BLINCYTO use in pregnant women. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier. Advise pregnant women of the potential risk to a fetus.

 

• The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

• Due to the potential for B-cell lymphocytopenia in infants following exposure to BLINCYTO in-utero, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination.

Data

Animal Data

• Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.

 

08/30/2016 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Immunization (addition)

• The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.

 

Pancreatitis (addition)

• Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting.

• Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone.

6 Adverse Reactions

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of BLINCYTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Fatal pancreatitis, has been reported in patients receiving BLINCYTO in combination with dexamethasone.

 

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG

BLINCYTO may cause serious side effects, including:

• The most common side effects of BLINCYTO include: (addition of the following)

  • low blood potassium (hypokalemia)

  • low red blood cell count (anemia)

  • low platelet count (thrombocytopenia)

  • stomach pain

PCI

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Cytokine Release Syndrome (CRS)

• Advise patients of the risk of CRS and infusion reactions, and to contact their healthcare professional for signs and symptoms associated with CRS or infusion reactions (pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing) to a healthcare professional.

Neurological Toxicities

• Advise patients of the risk of neurological toxicities, and to contact their healthcare professional for signs and symptoms associated with this event (convulsions, speech disorders, and confusion) to a healthcare professional.

Infections

Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection. Inform patients of the importance of keeping the skin clean around the intravenous catheter to reduce the risk of infection.

Pancreatitis

• Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis which include severe and persistent stomach pain, with or without nausea and vomiting.

Driving and Engaging in Hazardous Occupations

• Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events.

Reduce Risk of Infusion Pump Errors

• Inform patients they should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors. If there is a problem with the infusion pump or the pump alarms, patients should contact their doctor or nurse immediately.