FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES
1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1     Dosage
2.2     Administration
2.3     Dosage Adjustments
2.4     Reconstitution and Preparation of Solution for Infusion
2.5     Storage Requirements
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1     Cytokine Release Syndrome
5.2     Neurological Toxicities
5.3     Infections
5.4     Tumor Lysis Syndrome
5.5     Neutropenia and Febrile Neutropenia
5.6     Effects on Ability to Drive and Use Machines
5.7     Elevated Liver Enzymes
5.8     Leukoencephalopathy
5.9     Preparation and Administration Errors
6. ADVERSE REACTIONS
6.1     Clinical Trials Experience
6.2     Immunogenicity
7. DRUG INTERACTIONS
8. USE IN SPECIFIC POPULATIONS
8.1     Pregnancy
8.3     Lactation
8.4     Pediatric Use
8.5     Geriatric Use
8.6     Hepatic Impairment
8.7     Renal Impairment
10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY
12.1     Mechanism of Action
12.2     Pharmacodynamics
12.3     Pharmacokinetics
13. NONCLINICAL TOXICOLOGY
13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility
14. CLINICAL STUDIES
14.1     Acute Lymphoblastic Leukemia
16. HOW SUPPLIED/STORAGE AND HANDLING
16.1     How Supplied
16.2     Storage and Handling
17. PATIENT COUNSELING INFORMATION
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES
•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).
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 (14.1)].
2. DOSAGE AND ADMINISTRATION
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 reinitiation (eg, if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
Do not flush the BLINCYTO infusion line especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof.  Preparation and administration errors resulting in overdose have occurred [see Dosage and Administration (2.2 and 2.4) and Warnings and Precautions (5.9)].
2.1     Dosage
•A single cycle of treatment of BLINCYTO consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval.
•For patients at least 45 kg in weight:

-  In Cycle 1, administer BLINCYTO at 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8–28.
-  For subsequent cycles, administer BLINCYTO at 28 mcg/day on Days 1–28.
•Allow for at least 2 weeks treatment-free between cycles of BLINCYTO.
•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).
2.2     Administration
•Premedicate with dexamethasone 20 mg intravenously 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 day 8), or when restarting an infusion after an interruption of 4 or more hours.
•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.
•BLINCYTO infusion bags should be infused over 24 hours or 48 hours [see Dosage and Administration (2.4)]. Infuse the total 240 mL BLINCYTO solution according to the instructions on the pharmacy label on the bag at one of the following constant infusion rates:
-  Infusion rate of 10 mL/h for a duration of 24 hours, OR
-  Infusion rate of 5 mL/h for a duration of 48 hours
•The BLINCYTO solution for infusion 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 infusion line, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage. BLINCYTO should be infused through a dedicated lumen.
•At the end of the infusion, any unused BLINCYTO solution in the IV bag and IV lines should be disposed of in accordance with local requirements.
2.3     Dosage Adjustments
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.
*
Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening.
Toxicity
 Grade* 
 Action
 
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.
  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.
    
  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.
Grade 4 - Consider discontinuing BLINCYTO permanently.
2.4     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 (5.9)].
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO.
2.4.1    Gather Supplies
NOTE: 1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer.
Before preparation, ensure you have the following supplies ready:
•1 package of BLINCYTO for preparation of 9 mcg/day dose infused over 24 hours at a rate of 10 mL/h, 9 mcg/day dose infused over 48 hours at a rate of 5 mL/h, and 28 mcg/day dose infused over 24 hours at a rate of 10 mL/h
•2 packages of BLINCYTO for preparation of 28 mcg/day dose infused over 48 hours at a rate of 5 mL/h
The following supplies are also required, but not included in the package:
•Sterile, single-use disposable syringes
•21- to 23- gauge needle(s) (recommended)
•Preservative-free Sterile Water for Injection, USP
•250 mL 0.9% Sodium Chloride IV bag
◦To minimize the number of aseptic transfers, it is recommended to use a 250 mL-prefilled IV bag. 250 mL-prefilled IV bags typically contain overfill with a total volume of 265 to 275 mL. BLINCYTO dose calculations provided in section 2.4.4 are based on a starting volume of 265 mL to 275 mL 0.9% Sodium Chloride.
◦Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
•Polyolefin, PVC non-DEHP, 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.
2.4.2    Aseptic Preparation
Aseptic technique must be strictly observed 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:
•Preparation must be done in a USP <797> compliant facility.
•Preparation must be done in an ISO Class 5 laminar flow hood or better.
•The admixing area should have appropriate environmental specifications, confirmed by periodic monitoring.
•Personnel should be appropriately trained in aseptic manipulations and admixing of oncology drugs.
•Personnel should wear appropriate protective clothing and gloves.
•Gloves and surfaces should be disinfected.
2.4.3    SPECIAL CONSIDERATIONS TO SUPPORT ACCURATE PREPARATION
A) IV Solution Stabilizer is provided with the BLINCYTO package and is used to coat the prefilled IV bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to IV bags and IV lines. Therefore, add IV Solution Stabilizer to the IV bag containing 0.9% Sodium Chloride. Do not use IV Solution Stabilizer for reconstitution of BLINCYTO.
B) The entire volume of the admixed BLINCYTO will be more than the volume administered to the patient (240 mL) to account for the priming of the IV line and to ensure that the patient will receive the full dose of BLINCYTO.
C) When preparing an IV bag, remove air from IV bag. This is particularly important for use with an ambulatory infusion pump.
D) Use the specific volumes described in the admixing instructions [see Dosage and Administration (2.4.4)] to minimize errors in calculation.
2.4.4    Preparation of BLINCYTO Solution for Infusion Using a Prefilled 250 mL 0.9% Sodium Chloride IV Bag
Specific admixing instructions are provided for each dose and infusion time.  Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation section listed below.  Follow the steps for reconstituting BLINCYTO and preparing the IV bag.
•See section 2.4.4.1 for 9 mcg/day infused over 24 hours at a rate of 10 mL/h.
•See section 2.4.4.2 for 9 mcg/day infused over 48 hours at a rate of 5 mL/h.
•See section 2.4.4.3 for 28 mcg/day infused over 24 hours at a rate of 10 mL/h.
•See section 2.4.4.4 for 28 mcg/day infused over 48 hours at a rate of 5 mL/h.
2.4.4.1 Preparation of BLINCYTO 9 mcg/day infused over 24 hours at a rate of 10 mL/h
1.Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL.
2.Using a 10 mL syringe, aseptically transfer 5.5 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial.
3.Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake.
•Do not reconstitute BLINCYTO with IV Solution Stabilizer.
•The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL.
4.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.
5.Using a 1 mL syringe, aseptically transfer 0.83 mL of reconstituted BLINCYTO into the IV bag. Gently mix the contents of the bag to avoid foaming.
6.Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter.
7.Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride.
8.Store at 2°C to 8°C if not used immediately.
2.4.4.2 Preparation of BLINCYTO 9 mcg/day infused over 48 hours at a rate of 5 mL/h
1.Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL.
2.Using a 10 mL syringe, aseptically transfer 5.5 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial.
3.Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake.
•Do not reconstitute BLINCYTO with IV Solution Stabilizer.
•The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL.
4.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.
5.Using a 3 mL syringe, aseptically transfer 1.7 mL of reconstituted BLINCYTO into the IV bag. Gently mix the contents of the bag to avoid foaming.
6.Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter.
7.Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride.
8.Store at 2°C to 8°C if not used immediately.
2.4.4.3 Preparation of BLINCYTO 28 mcg/day infused over 24 hours at a rate of 10 mL/h
1.Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL.
2.Using a 10 mL syringe, aseptically transfer 5.6 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial.
3.Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of prese