Generic Name: blinatumomab
Dosage Form: injection
- Cytokine Release Syndrome (CRS), which may be life threatening or fatal, occurred in patients receiving Blincyto. Interrupt or discontinue Blincyto as recommended [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
- Neurological toxicities, 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)].
1 INDICATIONS AND USAGE
Blincyto is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) [see Dosage and Administration (2.1)].
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
• A single cycle of treatment of Blincyto consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• A treatment course consists of up to 2 cycles of Blincyto for induction followed by 3 additional cycles for consolidation treatment (up to a total of 5 cycles).
• See Table 1 for the recommended daily dose by patient weight. Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).
|Patient Weight||Cycle 1*||Subsequent Cycles*|
|Days 1-7||Days 8-28||Days 29-42||Days 1-28||Days 29-42|
Greater than or equal to 45 kg (fixed-dose)
|14-day treatment-free interval||
|14-day treatment-free interval|
|Less than 45 kg
(not to exceed 9 mcg/day)
(not to exceed 28 mcg/day)
(not to exceed 28 mcg/day)
*A single cycle of treatment of Blincyto consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• 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-initiation (eg, if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Premedicate with dexamethasone.
○ For adult patients, premedicate with 20 mg dexamethasone 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, 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.
• Administer Blincyto as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm.
• Prepared Blincyto infusion bags [see Dosage and Administration (2.4)] should be infused over 24 hours or 48 hours. The choice between 24 hours or 48 hours of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes.
• The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the IV tubing and to ensure that the patient will receive the full dose of Blincyto.
• Infuse Blincyto solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates:
- Infusion rate of 10 mL/hour for a duration of 24 hours, OR
- Infusion rate of 5 mL/hour for a duration of 48 hours
• The Blincyto solution must be administered using IV tubing that contains a sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter.
• Important Note: Do not flush the Blincyto infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, Blincyto should be infused through a dedicated lumen.
• At the end of the infusion, any unused Blincyto solution in the IV bag and IV tubing should be disposed of in accordance with local requirements.
If the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle.
|Toxicity||Grade*||Patients Greater Than
or Equal to 45 kg
|Patients Less Than 45 kg|
|Cytokine Release Syndrome (CRS)||Grade 3||Withhold Blincyto until resolved, then restart Blincyto at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur.
||Withhold Blincyto until resolved, then restart Blincyto at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur.
|Grade 4||Discontinue Blincyto permanently.
|Neurological Toxicity||Seizure||Discontinue Blincyto permanently if more than one seizure occurs.
|Grade 3||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 toxicity does not recur. If the toxicity occurred at 9 mcg/day, or if the toxicity 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 toxicity does not recur. If the toxicity occurred at 5 mcg/m2/day, or if the toxicity takes more than 7 days to resolve, discontinue Blincyto permanently.
|Grade 4||Discontinue Blincyto permanently.
|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 toxicity does not recur. If the toxicity 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 toxicity does not recur. If the toxicity takes more than 14 days to resolve, discontinue Blincyto permanently.
|Grade 4||Consider discontinuing Blincyto permanently.
|*Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.|
Reconstitution and Preparation of Solution for Infusion
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)].
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of Blincyto.
2.4.1 Aseptic Preparation
Strictly observe aseptic technique when preparing the solution for infusion since Blincyto vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare Blincyto according to aseptic standards, including but not limited to:
• Prepare Blincyto in a USP <797> compliant facility.
• Prepare Blincyto in an ISO Class 5 laminar flow hood or better.
• Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring.
• Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs.
• Ensure that personnel wear appropriate protective clothing and gloves.
• Ensure that gloves and surfaces are disinfected.
2.4.2 Gather Supplies
NOTE: 1 package Blincyto includes 1 vial of Blincyto and 1 vial of IV Solution Stabilizer.
• IV Solution Stabilizer is provided with the Blincyto package and is used to coat the IV bag prior to addition of reconstituted Blincyto to prevent adhesion of Blincyto to IV bags and IV tubing.
Before preparation, ensure you have the following supplies ready:
• 1 or 2 package(s) of Blincyto as needed for each dosage.
○ Patients weighing greater than or equal to 45 kg: 2 packages of Blincyto are needed for preparation of 28 mcg/day dose infused over 48 hours at a rate of 5 mL/hour
○ Patients weighing less than 45 kg: 2 packages of Blincyto are needed for preparation of 15 mcg/m2/day dose infused over 48 hours at a rate of 5 mL/hour for patients with a BSA greater than 1.09 m2
The following supplies are also required, but not included in the package:
• Supplies to make a 270 mL 0.9% Sodium Chloride IV bag
○ An empty IV bag. Use only PVC di-ethylhexylphthalate-free (DEHP-free), polyolefin, or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
○ 0.9% Sodium Chloride Injection , USP (eg, 1000 mL)
• Preservative-free Sterile Water for Injection, USP
• Sterile, single-use disposable syringes
• 21-to 23-gauge needle(s) (recommended)
• PVC DEHP-free, polyolefin, or EVA IV tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter
○ Ensure that the IV tubing is compatible with the infusion pump.
2.4.3 Reconstitution of Blincyto
1. Add 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the Blincyto vial and not directly on the lyophilized powder (resulting in a final Blincyto concentration of 12.5 mcg/mL).
• Do not reconstitute Blincyto with IV Solution Stabilizer.
2. Gently swirl contents to avoid excess foaming. Do not shake.
3. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated.
2.4.4 Preparation of Blincyto Infusion Bag
Verify the prescribed dose and infusion duration for each Blincyto infusion bag. To minimize errors, use the specific volumes described in Tables 2 to 4 to prepare the Blincyto infusion bag.
• Table 2 for patients weighing greater than or equal to 45 kg
• Tables 3 and 4 for patients weighing less than 45 kg
1. Aseptically add 270 mL 0.9% Sodium Chloride Injection, USP to the IV bag prior to the addition of IV Solution Stabilizer and reconstituted Blincyto.
• Use only PVC DEHP-free, polyolefin, or EVA IV bags/pump cassettes
2. Aseptically transfer 5.5 mL IV Solution Stabilizer to the IV bag containing 0.9% Sodium Chloride Injection, USP. Gently mix the contents of the bag to avoid foaming. Discard the vial containing the unused IV Solution Stabilizer.
3. Aseptically transfer reconstituted Blincyto into the IV bag containing 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. Gently mix the contents of the bag to avoid foaming.
• Refer to Tables 2 to 4 for the specific volume of reconstituted Blincyto
4. Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter.
• Use only PVC DEHP-free, polyolefin, or EVA IV tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter
• Ensure that the IV tubing is compatible with the infusion pump
5. Remove air from the IV bag. This is particularly important for use with an ambulatory infusion pump. Prime the IV tubing only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride Injection, USP.
6. Store at 2°C to 8°C if not used immediately [see Dosage and Administration (2.5)].
|0.9% Sodium Chloride Injection, USP (starting volume)||270 mL|
|IV Solution Stabilizer||5.5 mL|
|Dose||Infusion Duration||Infusion Rate||Reconstituted
|9 mcg/day||24 hours||10 mL/hour||0.83 mL|
|48 hours||5 mL/hour||1.7 mL|
|28 mcg/day||24 hours||10 mL/hour||2.6 mL|
|48 hours||5 mL/hour||5.2 mL*|
* 2 packages of Blincyto are needed for preparation of 28 mcg/day dose infused over 48 hours at a rate of 5 mL/hour.
|0.9% Sodium Chloride Injection, USP (starting volume)||270 mL|
|IV Solution Stabilizer||5.5 mL|
|Dose||Infusion Duration||Infusion Rate||BSA (m2)||Reconstituted Blincyto|
|5 mcg/m2/day||24 hours||10 mL/hour||1.5 – 1.59||0.7 mL|
|1.4 – 1.49||0.66 mL|
|1.3 – 1.39||0.61 mL|
|1.2 – 1.29||0.56 mL|
|1.1 – 1.19||0.52 mL|
|1 – 1.09||0.47 mL|
|0.9 – 0.99||0.43 mL|
|0.8 – 0.89||0.38 mL|
|0.7 – 0.79||0.33 mL|
|0.6 – 0.69||0.29 mL|
|0.5 – 0.59||0.24 mL|
|0.4 – 0.49||0.2 mL|
|48 hours||5 mL/hour||1.5 – 1.59||1.4 mL|
|1.4 – 1.49||1.3 mL|
|1.3 – 1.39||1.2 mL|
|1.2 – 1.29||1.1 mL|
|1.1 – 1.19||1 mL|
|1 – 1.09||0.94 mL|
|0.9 – 0.99||0.85 mL|
|0.8 – 0.89||0.76 mL|
|0.7 – 0.79||0.67 mL|
|0.6 – 0.69||0.57 mL|
|0.5 – 0.59||0.48 mL|
|0.4 – 0.49||0.39 mL|
|0.9% Sodium Chloride Injection, USP (starting volume)||270 mL|
|IV Solution Stabilizer||5.5 mL|
|Dose||Infusion Duration||Infusion Rate||BSA (m2)||Reconstituted Blincyto|
|15 mcg/m2/day||24 hours||10 mL/hour||1.5 – 1.59||2.1 mL|
|1.4 – 1.49||2 mL|
|1.3 – 1.39||1.8 mL|
|1.2 – 1.29||1.7 mL|
|1.1 – 1.19||1.6 mL|
|1 – 1.09||1.4 mL|
|0.9 – 0.99||1.3 mL|
|0.8 – 0.89||1.1 mL|
|0.7 – 0.79||1 mL|
|0.6 – 0.69||0.86 mL|
|0.5 – 0.59||0.72 mL|
|0.4 – 0.49||0.59 mL|
|48 hours||5 mL/hour||1.5 – 1.59||4.2 mL*|
|1.4 – 1.49||3.9 mL*|
|1.3 – 1.39||3.7 mL*|
|1.2 – 1.29||3.4 mL*|
|1.1 – 1.19||3.1 mL*|
|1 – 1.09||2.8 mL|
|0.9 – 0.99||2.6 mL|
|0.8 – 0.89||2.3 mL|
|0.7 – 0.79||2 mL|
|0.6 – 0.69||1.7 mL|
|0.5 – 0.59||1.4 mL|
|0.4 – 0.49||1.2 mL|
*2 packages of Blincyto are needed for preparation of 15 mcg/m2/day dose infused over 48 hours at a rate of 5 mL/hour for patients with a BSA greater than 1.09 m2.
The information in Table 5 indicates the storage time for the reconstituted Blincyto vial and prepared infusion bag.
Store lyophilized Blincyto and IV Solution Stabilizer vials for a maximum of 8 hours at room temperature in the original carton to protect from light [see How Supplied/Storage and Handling (16.2)].
|Maximum Storage Time
of Reconstituted Blincyto Vial
|Maximum Storage Time
of Prepared Blincyto Infusion Bag
23°C to 27°C
(73°F to 81°F)
2°C to 8°C
(36°F to 46°F)
|Room Temperature 23°C to 27°C
(73°F to 81°F)
2°C to 8°C
(36°F to 46°F)
|4 hours||24 hours||48 hours*||8 days|
|* Storage time includes infusion time. If IV bag containing Blincyto solution for infusion is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again.
3 DOSAGE FORMS AND STRENGTHS
For injection: 35 mcg of lyophilized powder in a single-dose vial for reconstitution.
Blincyto is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.
5 WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome
Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving Blincyto.
Infusion reactions have occurred with the Blincyto infusion and may be clinically indistinguishable from manifestations of CRS.
Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to Blincyto discontinuation. Life-threatening or fatal CRS was reported in patients receiving Blincyto. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS.
Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of Blincyto [see Dosage and Administration (2.3)].
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 [see Use in Specific Populations (8.4, 8.5)]. 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, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of Blincyto, but some resulted in treatment discontinuation.
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.
Monitor patients receiving Blincyto for signs and symptoms of neurological toxicities, and interrupt or discontinue Blincyto as recommended [see Dosage and Administration (2.3)].
In patients receiving Blincyto in clinical trials, 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. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with Blincyto. Monitor patients for signs and symptoms of infection and treat appropriately.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving Blincyto. 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 (2.3)].
Neutropenia and Febrile Neutropenia
Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving Blincyto. 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.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including seizures, 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.
Elevated Liver Enzymes
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.
Fatal pancreatitis has been reported in patients receiving Blincyto in combination with dexamethasone in clinical trials and the postmarketing setting.
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 (2.3)].
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.
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 (2.4)].
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.
6. ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
- Cytokine Release Syndrome [see Warnings and Precautions (5.1)]
- Neurological Toxicities [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)]
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 (≥ 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 [see Use in Special Populations (8.4, 8.5)].
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% of 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 ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher are summarized in Table 6.
|Adverse Reaction||Patients Greater Than
or Equal to 45 kg
(N = 225)
|Patients Less Than 45 kg
(N = 57)
|Grade 3 or Higher1
|Grade 3 or Higher1
|Blood and lymphatic system disorders|
|General disorders and administration site conditions|
|Immune system disorders|
|Cytokine release syndrome11||13||3||11||4|
|Infections and infestations|
|Infections – pathogen unspecified12||45||27||42||21|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||12||1||11||4|
|Nervous system disorders|
|Altered state of consciousness18||10||1||7||4|
|Respiratory, thoracic, and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
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.
|Patients Greater Than
or Equal to 45 kg
Grade 3 or 4 (%)
|Patients Less Than 45 kg
Grade 3 or 4 (%)
|Decreased lymphocyte count||90||88|
|Decreased white blood cell count||63||79|
|Decreased neutrophil count||67||97|
|Decreased platelet count||57||74|
1 Includes only patients who had both baseline and at least one laboratory measurement during the study available.
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 [see Warnings and Precautions (5.8)].
As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Blincyto has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
In clinical studies, less than 1% of patients treated with Blincyto tested positive for binding anti-blinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies. Anti-blinatumomab antibody formation may affect pharmacokinetics of Blincyto.
If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing.
The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading.
7 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 these patients, monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2, 12.3)].
8 USE IN SPECIFIC POPULATIONS
Based on its mechanism of action, Blincyto may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no data on the use of Blincyto in pregnant women. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier [see Data]. 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.
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. [see Warnings and Precautions (5.11)].
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.
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.
Females and Males of Reproductive Potential
Based on its mechanism of action, Blincyto may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Verify the pregnancy status of females of reproductive potential prior to initiating Blincyto treatment.
Advise females of reproductive potential to use effective contraception during treatment and for at least 48 hours after the last dose of Blincyto.
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 [see Adverse Reactions (6.1)]. 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.
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 [see Warnings and Precautions (5.2, 5.3)].
Overdoses have been observed, including one adult patient who received 133-fold the recommended therapeutic dose of Blincyto delivered over a short duration.
In the dose evaluation phase of the Phase 1/2 study in pediatric and adolescent patients with relapsed or refractory B-cell precursor ALL, 1 patient experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS) at a 30 mcg/m2/day (higher than the maximum tolerated/recommended) dose [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care [see Warnings and Precautions (5.10)]. Consider re-initiation of Blincyto at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion [see Dosage and Administration (2.1)].
Blincyto (blinatumomab) is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 (expressed on cells of B-lineage origin) and CD3 (expressed on T cells). Blincyto is produced in Chinese hamster ovary cells. It consists of 504 amino acids and has a molecular weight of approximately 54 kilodaltons.
Each Blincyto package contains 1 vial Blincyto and 1 vial IV Solution Stabilizer.
Blincyto is supplied in a single-dose vial as a sterile, preservative-free, white to off-white lyophilized powder for intravenous administration. Each single-dose vial of Blincyto contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust pH to 7.0. After reconstitution with 3 mL of preservative-free Sterile Water for Injection, USP, the resulting concentration is 12.5 mcg/mL blinatumomab.
IV Solution Stabilizer is supplied in a single-dose vial as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each single-dose vial of IV Solution Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride (2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and water for injection.
12 CLINICAL PHARMACOLOGY
Mechanism of Action
Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.
During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B cells, and transient cytokine elevation.
Peripheral T cell redistribution (ie, T cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of Blincyto infusion or dose escalation. T cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in majority of patients. Increase of T cell counts above baseline (T cell expansion) was observed in few patients.
Peripheral B cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week Blincyto-free period between treatment cycles. Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses.
Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of Blincyto infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.
The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.
The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with continuous intravenous infusion of blinatumomab.
The metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, Blincyto is expected to be degraded into small peptides and amino acids via catabolic pathways.
The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.
Gender, Age, and Body Surface Area
Results of population pharmacokinetic analyses indicate that age (0.62 to 80 years of age) and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to 2.70 m2) influences the pharmacokinetics of blinatumomab, however the clinical relevance of this effect is unknown.
No formal pharmacokinetic studies using Blincyto have been conducted in patients with hepatic impairment.
No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.
Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal impairment (CrCL ranging from 30 to 59 mL/min, N = 21) and normal renal function (CrCL more than 90 mL/min, N = 215). However, high interpatient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL less than 30 mL/min) or patients on hemodialysis.
Pediatrics: The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in pediatric patients. At the recommended doses, the mean (SD) steady state concentration (Css) values were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m2/day doses, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 3.91 (3.36) L/m2, 1.88 (1.90) L/hour/m2 and 2.19 (1.53) hours, respectively.
13 NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with blinatumomab.
No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice.
14. CLINICAL STUDIES
Relapsed/Refractory Acute Lymphoblastic Leukemia
Study 1 was an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation [HSCT], and had ≥ 10% blasts in bone marrow).
Blincyto was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 185 patients who received at least 1 infusion of Blincyto; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to Blincyto but later relapsed had the option to be retreated with Blincyto. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving Blincyto, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies.
Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with Blincyto. Seventy-seven out of 185 (41.6%) evaluable patients achieved CR/CRh* within the first 2 treatment cycles, with the majority of responses (81%, 62 out of 77) occurring within Cycle 1 of treatment. See Table 8 for efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77).
|N = 185|
[25.7 – 39.7]
[5.4 – 14.3]
[34.4 – 49.1]
[67.7 – 89.2]
[32.9 – 81.6]
[64.2 – 84.4]
|Median (months) (range)||6.7 (0.46 – 16.5)||5.0 (0.13 – 8.8)||5.9 (0.13 – 16.5)|
Study 2 was an open-label, multicenter, single-arm study in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or refractory to other treatments, and had > 25% blasts in bone marrow). Blincyto was administered at 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to Blincyto but later relapsed had the option to be retreated with Blincyto.
Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving Blincyto, and 39 out of 70 (55.7%) had refractory disease. The median number of treatment cycles was 1 (range: 1 to 5).
Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within cycle 1 of treatment. See Table 9 for the efficacy results from the study. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23).
|N = 70|
[9.2 – 28.0]
[8.1 – 26.4]
[22.1 – 45.1]
[21.1 – 78.9]
[10.9 – 69.2]
[23.2 – 65.5]
|Median (months) (range)||6.0 (0.5 – 12.1)||3.5 (0.5 – 16.4)||6.0 (0.5 – 16.4)|
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Blincyto package (NDC 55513-160-01) contains:
- One Blincyto 35 mcg single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and
- One IV Solution Stabilizer 10 mL single-dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. Do not use the IV Solution Stabilizer to reconstitute Blincyto.
Storage and Handling
Store Blincyto and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze.
Store and transport the prepared IV bag containing Blincyto solution for infusion at 2°C to 8°C (36°F to 46°F) conditions. Ship in packaging that has been validated to maintain temperature of the contents at 2°C to 8°C (36°F to 46°F). Do not freeze.
17 PATIENT COUNSELING INFORMATION
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) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
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) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Inform patients of the importance of keeping the skin clean around the intravenous catheter to reduce the risk of infection.
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 [see Warnings and Precautions (5.8) and Adverse Reactions (6.2)].
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 [see Warnings and Precautions (5.6)].
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.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
U.S. License No. 1080
© 2014-2016 Amgen Inc. All rights reserved.
Blincyto® (blin sye' toe)
|What is the most important information I should know about Blincyto?
Call your healthcare provider or get emergency medical help right away if you get any of the symptoms listed below.
Blincyto may cause serious side effects that can be severe, life-threatening, or lead to death, including:
See “What are the possible side effects of Blincyto?” below for other side effects of Blincyto.
|What is Blincyto?
Blincyto is a prescription medicine used to treat a certain type of acute lymphoblastic leukemia (ALL). ALL is a cancer of the blood in which a particular kind of white blood cell is growing out of control.
|Who should not receive Blincyto?
Do not receive Blincyto if you are allergic to blinatumomab or to any of the ingredients of Blincyto. See the end of this Medication Guide for a complete list of ingredients in Blincyto.
|What should I tell my healthcare provider before receiving Blincyto?
Before receiving Blincyto, tell your healthcare provider about all of your medical conditions, including if you or your child:
|How will I receive Blincyto?
|What should I avoid while receiving Blincyto?
Do not drive, operate heavy machinery, or do other dangerous activities while you are receiving Blincyto because Blincyto can cause neurological symptoms, such as dizziness, seizures, and confusion.
|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?”
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
|How should I store Blincyto?
Intravenous (IV) bags containing Blincyto for infusion will arrive in a special package.
|General information about 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.
|What are the ingredients in Blincyto?
Active ingredient: blinatumomab
Inactive ingredients: citric acid monohydrate, lysine hydrochloride, polysorbate 80, trehalose dihydrate, sodium hydroxide and preservative-free sterile water for injection.
|Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799
U.S. License No. 1080 © 2014-2016 Amgen Inc. All rights reserved. 1xxxxxx – v2
For more information, go to www.Blincyto.com or call Amgen at 1-800-772-6436.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 8/2016
PRINCIPAL DISPLAY PANEL
1 Blincyto® Single-Dose Vial
1 IV Solution Stabilizer Vial
For Intravenous Infusion Only
Store at 2°C to 8°C (36°F to 46°F).
Store in carton to protect from light.
DO NOT SHAKE reconstituted solution.
Dispense the enclosed Medication Guide to each patient.
Single-Dose Vial –
Discard unused portion.
|Labeler - Amgen Inc (039976196)|