Dosage & Administration
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Blincyto Prescribing Information
- Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
- Neurological toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [see Dosage and Administration (2.4), Warnings and Precautions (5.2)].
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.
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.
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).
| 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.
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.
| 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.
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 3 and 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).
| 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.
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.
| Adverse Reaction | Grade * | Patients Weighing 45 kg or More | Patients Weighing Less Than 45 kg |
|---|---|---|---|
| |||
| Cytokine Release Syndrome (CRS) | Grade 3 |
|
|
| 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. | ||
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.
Storage of Reconstituted BLINCYTO
The information in Table 5 indicates the storage time for the reconstituted BLINCYTO vial and prepared 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 * | 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 |
For injection: 35 mcg of white to off-white lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
Risk Summary
Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of BLINCYTO in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier (see Data).
Blinatumomab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD19 on B-cells and the finding of B-cell depletion in non-pregnant animals, blinatumomab can cause B-cell lymphocytopenia in infants exposed to blinatumomab in-utero. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Due to the potential for B-cell lymphocytopenia in infants following exposure to BLINCYTO in utero, the infant's B lymphocytes should be monitored before the initiation of live virus vaccination [see Warnings and Precautions (5.11)].
Data
Animal Data
Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.
Lactation
Risk Summary
There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose.
Females and Males of Reproductive Potential
BLINCYTO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose.
Pediatric Use
The safety and efficacy of BLINCYTO in pediatric patients less than 1 month of age have not been established for any indication [see Indications and Usage (1)].
Minimal Residual Disease (MRD)-Positive B-cell Precursor ALL
The safety and efficacy of BLINCYTO for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% have been established in pediatric patients one month and older. Use of BLINCYTO is supported by evidence from two randomized, controlled trials (Study AALL1331, NCT02101853 and Study 20120215, NCT02393859) [see Clinical Studies (14.3)] in pediatric patients with first relapsed B-cell precursor ALL. Both studies included pediatric patients with MRD-positive B-cell precursor ALL. The studies included pediatric patients treated with BLINCYTO in the following age groups: 6 infants (1 month up to less than 2 years), 165 children (2 years up to less than 12 years), and 70 adolescents (12 years to less than 17 years). In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with MRD-positive ALL [see Adverse Reactions (6.1)], and no differences in safety were observed between the different pediatric age subgroups.
Relapsed or Refractory B-cell Precursor ALL
The safety and efficacy of BLINCYTO have been established in pediatric patients one month and older with relapsed or refractory B-cell precursor ALL. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups [see Clinical Studies (14.2)].
In general, the adverse reactions in BLINCYTO-treated pediatric patients with relapsed or refractory ALL were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL [see Adverse Reactions (6.1)]. Adverse reactions that were observed more frequently (≥ 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants) with relapsed or refractory ALL, the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
B-cell Precursor ALL in the Consolidation Phase
The safety and efficacy of BLINCYTO for the treatment of Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients one month and older. Use of BLINCYTO for this indication is supported by extrapolation from a randomized controlled study in adults (Study E1910, NCT02003222) and evidence from two randomized, controlled studies in pediatric patients (Study 20120215 and Study AALL1331) [see Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
Benzyl Alcohol Toxicity in Neonates
Serious and fatal adverse reactions, including "gasping syndrome," can occur in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) treated with benzyl alcohol-preserved drugs intravenously. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (blood concentration of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known [see Warnings and Precautions (5.12)].
Use the preservative-free formulations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative). The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Warnings and Precautions (5.12)].
Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance. Monitor these patients during use of BLINCYTO (with preservative) for new or worsening metabolic acidosis.
Geriatric Use
There were 158 (7%) patients 65 years and older in clinical studies of BLINCYTO for patients with MRD positive, CD19-positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19-positive B-cell precursor ALL, and CD19-positive, Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase. Of the total number of BLINCYTO-treated patients in these studies, 123 (8%) were 65 years of age and older and 21 (1%) were 75 years of age or older. 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 serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion [see Warnings and Precautions (5.2, 5.3)].
BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.