Blincyto (Blinatumomab) Kit [Amgen, Inc]
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These highlights do not include all the information needed to use BLINCYTO® safely and effectively. See full prescribing information for BLINCYTO. BLINCYTO® (blinatumomab) for injection, for intravenous use Initial U.S. Approval:…
Active ingredients
Manufacturer
Strength12.5 ug / 1 mL
Dosage formKIT
Registration number55513-150-01
Uses and indications
BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adult and pediatric patients one month and older with:
• 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%. (1.1)
• Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL)…
• 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%. (1.1)
• Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL)…
BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adult and pediatric patients one month and older with:
• 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%. (1.1)
• Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). (1.2)
• CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy. (1.3) 1.1 MRD-positive B-cell Precursor ALL
BLINCYTO is indicated 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% in adult and pediatric patients one month and older. 1.2 Relapsed or Refractory B-cell Precursor ALL
BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one month and older. 1.3 B-cell Precursor ALL in the Consolidation Phase
BLINCYTO is indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy in adult and pediatric patients one month and older.
• 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%. (1.1)
• Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). (1.2)
• CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy. (1.3) 1.1 MRD-positive B-cell Precursor ALL
BLINCYTO is indicated 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% in adult and pediatric patients one month and older. 1.2 Relapsed or Refractory B-cell Precursor ALL
BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one month and older. 1.3 B-cell Precursor ALL in the Consolidation Phase
BLINCYTO is indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy in adult and pediatric patients one month and older.
Contraindications
BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.
Side effects
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse…
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse…
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently.
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Cytokine Release Syndrome
[see Warnings and Precautions (5.1)]
• Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome
[see Warnings and Precautions (5.2)]
• Infections
[see Warnings and Precautions (5.3)]
• Tumor Lysis Syndrome
[see Warnings and Precautions (5.4)]
• Neutropenia and Febrile Neutropenia
[see Warnings and Precautions (5.5)]
• Effects on Ability to Drive and Use Machines
[see Warnings and Precautions (5.6)]
• Elevated Liver Enzymes
[see Warnings and Precautions (5.7)]
• Pancreatitis
[see Warnings and Precautions (5.8)]
• Leukoencephalopathy
[see Warnings and Precautions (5.9)]
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently.
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Cytokine Release Syndrome
[see Warnings and Precautions (5.1)]
• Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome
[see Warnings and Precautions (5.2)]
• Infections
[see Warnings and Precautions (5.3)]
• Tumor Lysis Syndrome
[see Warnings and Precautions (5.4)]
• Neutropenia and Febrile Neutropenia
[see Warnings and Precautions (5.5)]
• Effects on Ability to Drive and Use Machines
[see Warnings and Precautions (5.6)]
• Elevated Liver Enzymes
[see Warnings and Precautions (5.7)]
• Pancreatitis
[see Warnings and Precautions (5.8)]
• Leukoencephalopathy
[see Warnings and Precautions (5.9)]
Precautions
• Infections: Monitor patients for signs or symptoms; treat appropriately. (5.3)
• Effects on Ability to Drive and Use Machines: 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. (5.6)
• Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management…
• Effects on Ability to Drive and Use Machines: 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. (5.6)
• Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management…
• Infections: Monitor patients for signs or symptoms; treat appropriately. (5.3)
• Effects on Ability to Drive and Use Machines: 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. (5.6)
• Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO. (5.8)
• Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration. (5.10)
• Benzyl Alcohol Toxicity in Neonates: Use BLINCYTO prepared with preservative-free saline for neonates. BLINCYTO solution containing benzyl alcohol is not recommended for patients weighing less than 5.4 kg. (5.12, 8.4)
• Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.13, 8.1, 8.3) 5.1 Cytokine Release Syndrome
Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. 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 fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC). 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. 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)]
.
Monitor patients for signs or symptoms of these events. Advise outpatients on BLINCYTO to contact their healthcare professional for signs and symptoms associated with CRS. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS
[see Dosage and Administration (2.4)]
. 5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome
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 (≥ 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. 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.
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)]
. 5.3 Infections
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
[see Adverse Reactions (6.1)]
. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately. 5.4 Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO
[see Adverse Reactions (6.1)]
. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO
[see Dosage and Administration (2.4)]
. 5.5 Neutropenia and Febrile Neutropenia
Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO
[see Adverse Reactions (6.1)]
. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. 5.6 Effects on Ability to Drive and Use Machines
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. 5.7 Elevated Liver Enzymes
Treatment with BLINCYTO was associated with transient elevations in liver enzymes
[see Adverse Reactions (6.1)]
. 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.
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 total bilirubin rises to more than 3 times the upper limit of normal
. 5.8 Pancreatitis
Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting
[see Adverse Reactions (6.2)]
.
Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone
[see Dosage and Administration (2.4)]
. 5.9 Leukoencephalopathy
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 5.10 Preparation and Administration Errors
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose)
[see Dosage and Administration (2.5) and Instructions for Use]
. 5.11 Immunization
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. 5.12 Benzyl Alcohol Toxicity in Neonates
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 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)]
. 5.13 Embryo-Fetal Toxicity
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)]
.
• Effects on Ability to Drive and Use Machines: 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. (5.6)
• Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO. (5.8)
• Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration. (5.10)
• Benzyl Alcohol Toxicity in Neonates: Use BLINCYTO prepared with preservative-free saline for neonates. BLINCYTO solution containing benzyl alcohol is not recommended for patients weighing less than 5.4 kg. (5.12, 8.4)
• Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.13, 8.1, 8.3) 5.1 Cytokine Release Syndrome
Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. 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 fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC). 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. 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)]
.
Monitor patients for signs or symptoms of these events. Advise outpatients on BLINCYTO to contact their healthcare professional for signs and symptoms associated with CRS. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS
[see Dosage and Administration (2.4)]
. 5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome
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 (≥ 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. 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.
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)]
. 5.3 Infections
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
[see Adverse Reactions (6.1)]
. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately. 5.4 Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO
[see Adverse Reactions (6.1)]
. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO
[see Dosage and Administration (2.4)]
. 5.5 Neutropenia and Febrile Neutropenia
Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO
[see Adverse Reactions (6.1)]
. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. 5.6 Effects on Ability to Drive and Use Machines
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. 5.7 Elevated Liver Enzymes
Treatment with BLINCYTO was associated with transient elevations in liver enzymes
[see Adverse Reactions (6.1)]
. 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.
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 total bilirubin rises to more than 3 times the upper limit of normal
. 5.8 Pancreatitis
Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting
[see Adverse Reactions (6.2)]
.
Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone
[see Dosage and Administration (2.4)]
. 5.9 Leukoencephalopathy
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 5.10 Preparation and Administration Errors
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose)
[see Dosage and Administration (2.5) and Instructions for Use]
. 5.11 Immunization
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. 5.12 Benzyl Alcohol Toxicity in Neonates
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 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)]
. 5.13 Embryo-Fetal Toxicity
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)]
.
Dosage
• For the treatment of MRD-positive B-cell Precursor ALL
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.1)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.1)
-
Premedicate with prednisone or equivalent dexamethasone. (2.1)
• For the treatment of Relapsed or Refractory B-cell Precursor ALL
-
See…
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.1)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.1)
-
Premedicate with prednisone or equivalent dexamethasone. (2.1)
• For the treatment of Relapsed or Refractory B-cell Precursor ALL
-
See…
• For the treatment of MRD-positive B-cell Precursor ALL
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.1)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.1)
-
Premedicate with prednisone or equivalent dexamethasone. (2.1)
• For the treatment of Relapsed or Refractory B-cell Precursor ALL
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.2)
-
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. (2.2)
-
Premedicate with dexamethasone. (2.2)
• For the treatment of B-cell Precursor ALL in the Consolidation Phase
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.3)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.3)
-
Premedicate with dexamethasone. (2.3)
• Refer to Full Prescribing Information for important preparation and administration information. (2.5)
• Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump.
-
See Instructions for Use for infusion over 24 hours or 48 hours.
-
See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). This option is not recommended for patients weighing less than 5.4 kg. 2.1 Treatment of MRD-positive B-cell Precursor ALL
• A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• See Table 1 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose. For patients weighing less than 45 kg, the dose is calculated using the patient's body surface area (BSA).
Table 1. Recommended BLINCYTO Dose and Schedule for the Treatment of MRD-positive B-cell Precursor ALL
Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Induction Cycle 1
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Consolidation Cycles 2-4
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL:
• For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.2 Treatment of Relapsed or Refractory B-cell Precursor ALL
• A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).
• See Table 2 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA.
Table 2. Recommended BLINCYTO Dose and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL
Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Induction Cycle 1
Days 1-7
9 mcg/day
5 mcg/m2/day
(not to exceed 9 mcg/day)
Days 8-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Induction Cycle 2
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Consolidation Cycles 3-5
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Continued Therapy Cycles 6-9
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-84
56-day treatment-free interval
56-day treatment-free interval
• Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
• For adult patients, premedicate with 20 mg of dexamethasone intravenously or orally 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase
• A single cycle of BLINCYTO monotherapy in consolidation is 28 days of continuous infusion followed by a 14-day treatment-free interval (total 42 days)
[see Table 3and Clinical Studies (14.3)]
.
• Patients weighing 45 kg or more receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA (see Table 3).
Table 3. Recommended BLINCYTO Dose and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL
BLINCYTO Consolidation Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
• For adult patients, premedicate with dexamethasone 20 mg intravenously within 1 hour prior to the first dose of BLINCYTO of each cycle.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.4 Dosage Modifications for Adverse Reactions
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently. 2.5 Preparation and Administration of BLINCYTO
It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose)
[see Warnings and Precautions (5.10)]
.
BLINCYTO can be infused over 24 hours (preservative-free), 48 hours (preservative-free), 72 hours (with preservative), 96 hours (with preservative), or 7 days (with preservative). The choice between these options for the infusion duration should be made by the treating healthcare provider considering the frequency of the infusion bag changes and the weight of the patient. 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.
For preparation, reconstitution, and administration of BLINCYTO:
The BLINCYTO Instructions for Use contains more detailed instructions on the preparation of infusion
[see Instructions for Use]
.
The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO. 2.6 Storage of Reconstituted BLINCYTO
The information in Table 5 indicates the storage time for the reconstituted BLINCYTO vial and prepared infusion bag.
Table 5. Storage Time for Reconstituted BLINCYTO Vial and Prepared BLINCYTO Infusion Bag
Maximum Storage Time
Room Temperature
23°C to 27°C
(73°F to 81°F)
Refrigerated
2°C to 8°C
(36°F to 46°F)
Reconstituted BLINCYTO Vial
4 hours
24 hours
Prepared BLINCYTO 24-Hour and 48-Hour Infusion Bag
(Preservative-free)
48 hours
Storage time includes infusion time. If the prepared BLINCYTO infusion bag is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again.
8 days
Prepared BLINCYTO 72-Hour and 96-Hour Infusion Bag
(with Preservative)
4 days
14 days
Prepared BLINCYTO 7-Day Infusion Bag
(with Preservative)
7 days
14 days
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently.
For injection: 35 mcg of white to off-white lyophilized powder in a single-dose vial for reconstitution.
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.1)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.1)
-
Premedicate with prednisone or equivalent dexamethasone. (2.1)
• For the treatment of Relapsed or Refractory B-cell Precursor ALL
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.2)
-
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. (2.2)
-
Premedicate with dexamethasone. (2.2)
• For the treatment of B-cell Precursor ALL in the Consolidation Phase
-
See Full Prescribing Information for recommended dose by patient weight and schedule. (2.3)
-
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.3)
-
Premedicate with dexamethasone. (2.3)
• Refer to Full Prescribing Information for important preparation and administration information. (2.5)
• Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump.
-
See Instructions for Use for infusion over 24 hours or 48 hours.
-
See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). This option is not recommended for patients weighing less than 5.4 kg. 2.1 Treatment of MRD-positive B-cell Precursor ALL
• A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• See Table 1 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose. For patients weighing less than 45 kg, the dose is calculated using the patient's body surface area (BSA).
Table 1. Recommended BLINCYTO Dose and Schedule for the Treatment of MRD-positive B-cell Precursor ALL
Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Induction Cycle 1
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Consolidation Cycles 2-4
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL:
• For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.2 Treatment of Relapsed or Refractory B-cell Precursor ALL
• A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).
• See Table 2 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA.
Table 2. Recommended BLINCYTO Dose and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL
Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Induction Cycle 1
Days 1-7
9 mcg/day
5 mcg/m2/day
(not to exceed 9 mcg/day)
Days 8-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Induction Cycle 2
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Consolidation Cycles 3-5
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
Continued Therapy Cycles 6-9
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-84
56-day treatment-free interval
56-day treatment-free interval
• Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
• For adult patients, premedicate with 20 mg of dexamethasone intravenously or orally 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase
• A single cycle of BLINCYTO monotherapy in consolidation is 28 days of continuous infusion followed by a 14-day treatment-free interval (total 42 days)
[see Table 3and Clinical Studies (14.3)]
.
• Patients weighing 45 kg or more receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA (see Table 3).
Table 3. Recommended BLINCYTO Dose and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL
BLINCYTO Consolidation Cycle
Patients Weighing 45 kg or More
(Fixed-dose)
Patients Weighing Less Than 45 kg
(BSA-based dose)
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)
Days 29-42
14-day treatment-free interval
14-day treatment-free interval
• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
• For adult patients, premedicate with dexamethasone 20 mg intravenously within 1 hour prior to the first dose of BLINCYTO of each cycle.
• For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
• See Instructions for Use for infusion over 24 hours or 48 hours.
• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). 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. 2.4 Dosage Modifications for Adverse Reactions
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently. 2.5 Preparation and Administration of BLINCYTO
It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose)
[see Warnings and Precautions (5.10)]
.
BLINCYTO can be infused over 24 hours (preservative-free), 48 hours (preservative-free), 72 hours (with preservative), 96 hours (with preservative), or 7 days (with preservative). The choice between these options for the infusion duration should be made by the treating healthcare provider considering the frequency of the infusion bag changes and the weight of the patient. 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.
For preparation, reconstitution, and administration of BLINCYTO:
The BLINCYTO Instructions for Use contains more detailed instructions on the preparation of infusion
[see Instructions for Use]
.
The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO. 2.6 Storage of Reconstituted BLINCYTO
The information in Table 5 indicates the storage time for the reconstituted BLINCYTO vial and prepared infusion bag.
Table 5. Storage Time for Reconstituted BLINCYTO Vial and Prepared BLINCYTO Infusion Bag
Maximum Storage Time
Room Temperature
23°C to 27°C
(73°F to 81°F)
Refrigerated
2°C to 8°C
(36°F to 46°F)
Reconstituted BLINCYTO Vial
4 hours
24 hours
Prepared BLINCYTO 24-Hour and 48-Hour Infusion Bag
(Preservative-free)
48 hours
Storage time includes infusion time. If the prepared BLINCYTO infusion bag is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again.
8 days
Prepared BLINCYTO 72-Hour and 96-Hour Infusion Bag
(with Preservative)
4 days
14 days
Prepared BLINCYTO 7-Day Infusion Bag
(with Preservative)
7 days
14 days
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 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.
Table 4. Dosage Modifications for Adverse Reactions
Adverse Reaction
Grade
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Patients Weighing 45 kg or More
Patients Weighing Less Than 45 kg
Cytokine Release Syndrome (CRS)
Grade 3
• Interrupt BLINCYTO.
• Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
• Interrupt BLINCYTO.
• Administer dexamethasone 5 mg/m2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.
• When CRS is resolved, restart BLINCYTO at 5 mcg/m2/day, and escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 4
Discontinue BLINCYTO permanently. Administer dexamethasone as instructed for Grade 3 CRS.
Neurological Toxicity
Seizure
Discontinue BLINCYTO permanently if more than one seizure occurs.
Grade 2 ICANS
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 9 mcg/day.
Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.
Interrupt BLINCYTO until ICANS resolves.
Administer corticosteroids and manage according to current practice guidelines.
When ICANS is resolved, restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur.
Grade 3 Neurologic Events including ICANS
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Grade 4
Discontinue BLINCYTO permanently.
Neurologic Events including ICANS
If ICANS, administer corticosteroids and manage according to current practice guidelines.
Other Clinically Relevant Adverse Reactions
Grade 3
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction takes more than 14 days to resolve, discontinue BLINCYTO permanently.
Grade 4
Consider discontinuing BLINCYTO permanently.
For injection: 35 mcg of white to off-white lyophilized powder in a single-dose vial for reconstitution.
Drug interactions
No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In…
No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (e.g., warfarin) or drug concentrations (e.g., cyclosporine). Adjust the dose of the concomitant drug as needed
[see Clinical Pharmacology (12.2, 12.3)]
.
[see Clinical Pharmacology (12.2, 12.3)]
.
References
Source: DailyMed, U.S. National Library of Medicine. Additional information compiled from online sources.
Important: The information on this page is provided for reference only and is not a substitute for diagnosis, prescribing, or treatment guidance from a doctor or pharmacist.
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