IMPORTANT RISK MINIMIZATION INFORMATION · Important Information Regarding BLINCYTO The following actions should be taken to prevent or minimize the risk of medication errors and

IMPORTANT RISK MINIMIZATION INFORMATION FOR HEALTHCARE PROFESSIONALS

This educational brochure contains important information regarding the administration of blinatumomab and the risks of medication errors, neurologic events and cytokine release syndrome

This educational material is essential to ensure the safe and effective use of the product and appropriate management of the important selected risks and therefore it is advised to be read carefully before prescribing, preparing and administering the medicine

PLEASE ENSURE EACH PATIENT OR CAREGIVER IS PROVIDED A COPY OF THE PATIENT EDUCATIONAL MATERIAL

The H.S.A.-approved Product Information for BLINCYTO® is appended to this document.

If you have any questions, require additional information regarding the use of BLINCYTO®, or to report any adverse events or product quality complaints, please contact:

Amgen Medical InformationTel.: 800 616 7094 | e-mail: [email protected]

IMPORTANT INFORMATION REGARDING

BLINCYTO® (BLINATUMOMAB) THERAPY

IMPORTANT RISK MINIMIZATION INFORMATION FOR PHYSICIANS • Approved BLINCYTO® Indication • Overview of BLINCYTO treatment • BLINCYTO dosage: Treatment of MRD-Positive B-cell Precursor ALL • BLINCYTO dosage: Treatment of Relapsed or Refractory B-cell Precursor ALL • Dose Adjustments • Medication Errors • Neurologic events • Cytokine Release (CRS)

IMPORTANT RISK MINIMISATION INFORMATION FOR PHARMACISTS Important information about the preparation of BLINCYTO intravenous administration

• Table 1. Materials required for the preparation of BLINCYTO infusion solution (For Patients Weighing Greater Than or Equal to 45 kg)

• Table 2. Materials required for the preparation of BLINCYTO infusion solution (For Patients Weighing Less Than 45kg) • Table 3. Steps to prepare BLINCYTO infusion solution under aseptic conditions using aseptic techniques

IMPORTANT RISK MINIMISATION INFORMATION FOR NURSES • Administration • Counseling

CONTENTS

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12

8

2

• Hospitalization is recommended for the fi rst 3 days of the fi rst cycle and the fi rst 2 days of the second cycle. For all subsequent cycle starts and re-initiations (eg, if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.

• Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL.

For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (eg, dexamethasone 16 mg) 1 hour prior to the fi rst dose of BLINCYTO in each cycle.

For pediatric patients, premedicate with 5 mg/m2 of dexamethasone, to a maximum dose of 20 mg prior to the fi rst dose of BLINCYTO in the fi rst cycle and when restarting an infusion after an interruption of 4 or more hours in the fi rst cycle.

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).

Recommended BLINCYTO Dosage and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL

PATIENT WEIGHTGreater Than or Equal to 45 kg

PATIENT WEIGHTLess Than 45 kgCycle

Days 1-7

Days 8-28

9 mcg/day

28 mcg/day

5 mcg/m2/day(not to exceed 9 mcg/day)


Days 29-42 14-day treatment-free interval 14-day treatment-free interval

Days 1-28

Days 29-42

28 mcg/day

14-day treatment-free interval



(BSA-based dose)(Fixed-dose)

(not to exceed 28 mcg/day)

InductionCycle 1

InductionCycle 2

Days 1-28

Days 29-42

28 mcg/day





Consolidation Cycles 3-5

Days 1-28

Days 29-42

28 mcg/day 15 mcg/m2/day(not to exceed 28 mcg/day)



Continued Therapy Cycles 6-9


IMPORTANT INFORMATION REGARDING BLINCYTO® (BLINATUMOMAB) THERAPY

IMPORTANT RISK MINIMIZATION INFORMATION FOR PHYSICIANS Approved BLINCYTO® IndicationBLINCYTO is indicated for the treatment of:

• B-cell precursor acute lymphoblastic leukemia (ALL), in fi rst or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.

• Relapsed or refractory B-cell precursor ALL in adults and children.

Overview of BLINCYTO treatment:Patients will receive BLINCYTO by continuous intravenous infusion.

• In patients with a history or presence of clinically relevant central nervous system (CNS)pathology (see Warnings and Precautions [5.2] of the Product Information), hospitalization is recommended at a minimum for the fi rst 14 days of the fi rst cycle. In the second cycle, hospitalization is recommended at a minimum for 2 days, and clinical judgement should be based on tolerance to blinatumomab in the fi rst cycle. Caution should be exercised as cases of late occurrence of fi rst neurological events in the second cycle have been observed.

• Recommended daily dose is by patient weight. Patients greater than or equal to 45 kg receive a fi xed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).

BLINCYTO dosage: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).

Recommended BLINCYTO Dosage and Schedule for the Treatment of MRD-Positive B-cell Precursor ALL

Cycle

Days 1-28

Days 29-42

28 mcg/day




Days 1-28

Days 29-42

28 mcg/day

14-day treatment-free interval 14-day treatment-free interval


PATIENT WEIGHTGreater Than or Equal to 45 kg

PATIENT WEIGHTLess Than 45 kg

(BSA-based dose)(Fixed-dose)

ConsolidationCycles 2-4

InductionCycle 1

3 4

MEDICATIONERRORS

• Medication errors are unintended errors in the prescribing, dispensing, or administration of a medicinal product while in the control of the healthcare professional or patient.

• Ensure that patients receive the recommended daily dose according to their 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). See Section 2, Dosage and Administration of the Product Information.

• To minimize the potential events of medication errors, please counsel patients on the following:

Instruct patients not to unlock the pump

If the pump does not appear to perform properly (for example: alarm goes off) at any time, instruct patients and caregivers not to try to fix the pump and tell them to contact you or the nurse immediately

Instruct patients not to change any pump settings on purpose (with the exception of stopping the pump in case of emergency)

• In addition, you can help by reporting any medication errors that you or your patients have encountered or experienced to Amgen, via the contact information provided in this material.

• Hospitalization is recommended for patients with a history or presence of clinically relevant CNS pathology:

At a minimum for the first 14 days of the first cycle (clinical judgement should be based on tolerance to BLINCYTO).

At a minimum for 2 days in the second cycle. Caution should be exercised as cases of late occurrence of first neurological events in the second cycle have been observed.• See Section 2.3 Dosage Adjustments of the Product Information for

management of severe (Grade 3) and life-threatening (Grade 4) neurologic events

• Monitor patients for signs and symptoms of neurologic events (eg, confusion, disorientation, dizziness, tremor, seizure) prior to and

throughout the treatment cycle. Manifestations of neurological toxicity also includes cranial nerve disorders. The majority of neurologic events resolved following interruption of BLINCYTO, but

some resulted in treatment discontinuation.• Consider utilizing a writing test periodically to evaluate for the early

detection of neurologic events• Be aware that elderly patients experience a higher rate of neurologic

events, including cognitive disorder, encephalopathy, and confusion

NEUROLOGIC EVENTS

• 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 intravenously 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 10 mg/m2 of dexamethasone (not to exceed 20 mg) orally or intravenously 6 to 12 hours prior to the start of BLINCYTO (Cycle 1 day 1), followed by dexamethasone 5 mg/m2 (not to exceed 20 mg) orally or intravenously within 30 minutes of the start of BLINCYTO (Cycle 1 day 1), 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.

In the case of toxicities, consideration can be made to interrupt or discontinue the infusion of BLINCYTO. Please refer to Dosage adjustments under section 2.3 Dosage Adjustments of the Product Information for further details.

If the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of28 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. If the toxicity does not resolve within 14 days, discontinue BLINCYTO permanently, except in those circumstances as described in the approved Product Information (Please refer to Dose Adjustments under 2.3 Dosage Adjustments).

Planned bag change frequency

Every 24 hours

Every 72 hoursEvery 48 hours

Every 96 hours

10 mL/hr

3.3 mL/hr5 mL/hr

2.5 mL/hr

Infusion rate

Dose Adjustments

Patients will receive continuous intravenous infusion of BLINCYTO. Discuss the infusion duration with your patients as there is a choice of bag change frequency. However, the target therapeutic dose of BLINCYTO delivered does not change.

5 6

The following actions should be taken to prevent or minimize the risk of medication errors, neurologic events and cytokine release syndrome.

• 1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer (see across table for required number of vials)

• Preservative-free sterile water for injections.

• Supplies to make a 270mL 0.9% Sodium Chloride IV bag (include an empty IV bag and 0.9% Sodium Chloride Injection, USP [eg, 1000mL])

• Sterile, single-use disposable syringes

• 21- to 23- gauge needle(s)

LIST OF MATERIALS

DOSE INFUSION DURATION

REQUIRED NUMBER OF BLINCYTO

VIALS

RECONSTITUTED BLINCYTO

SOLUTION (mL) FROM STEP 1

IMPORTANT INFORMATION ABOUT THE PREPARATION OF BLINCYTO INTRAVENOUS ADMINISTRATION

Table 1. Materials Required for the Preparation of BLINCYTO Infusion Solution (For Patients Weighing Greater Than or Equal to 45kg)

9microgram/

day

28microgram/

day

24 hours

24 hours

48 hours

72 hours

72 hours

96 hours

96 hours

48 hours

2.6 101

1.7

2.5

8

3.3

10.7

5

3.3

3.3

2.5

2.5

1

1

3

2

4

0.83 101

5.2 52

Use only polyolefi n, PVC di-ethylhexylphthalate-free (DEHP-free), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes and polyolefi n, PVC DEHP-free, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 µm in-line fi lter.

This educational brochure contains important information regarding the reconstitution and preparation procedures for BLINCYTO® (blinatumomab). To ensure the safe and eff ective use of the medicinal product and appropriate management of the important selected risks, please carefully read this material before reconstituting and preparing of the medicinal product.

If you have any questions about the reconstitution and preparation of blinatumomab please refer to the Product Information, which is provided with this educational brochure.

IMPORTANT RISK MINIMIZATION INFORMATION FOR PHARMACISTS

0.9% Sodium Chloride Injection, USP (starting volume) 270 mLIV Solution Stabilizer 5.5 mL

• Discontinue BLINCYTO permanently if more than one seizure occurs

• Withhold dose if Grade 3 (severe) neurologic event occurs and discontinue permanently if Grade 4 (life-threatening) neurologic event occurs

• The median time to the fi rst event was within the fi rst 2 weeks of BLINCYTO treatment, however symptoms may appear earlier or later• It is essential to counsel patients regarding the potential neurologic

eff ects and to advise patients:

Not to drive, operate heavy machines or engage in hazardous activities while receiving BLINCYTO

To contact you if they experience neurologic symptoms

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)

NEUROLOGIC EVENTS

(continued)

• Cytokine Release Syndrome (CRS) which may be life-threatening or fatal has been reported in patients receiving blinatumomab

• Monitor for signs and symptoms of CRS, some of which may be pyrexia, asthenia, headache, hypotension, total bilirubin increased, and nausea. In some cases, disseminated intravascular coagulation, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome have been reported in the setting of CRS

• The median time to onset of CRS was 2 days following start of BLINCYTO and the median time to resolution of CRS was 5 days among cases that resolved.

• Management of these events may require temporary interruption or permanent discontinuation of BLINCYTO.

If a Grade 3 non-neurologic event occurs, interrupt BLINCYTO and administer dexamethasone 5 mg/m2 (patients < 45 kg) or 8 mg (patients ≥ 45 kg) every 8 hours intravenously or orally for up to 3 days, and taper thereafter over 4 days.

If a Grade 4 non-neurologic event occurs, discontinue BLINCYTO

permanently. Administer dexamethasone as instructed for Grade 3 CRS.

CYTOKINE RELEASE

SYNDROME (CRS)

7 8

INFUSIONRATE (mL/hr)






LIST OF MATERIALS DOSE INFUSION DURATION BSA (m2)

INFUSIONRATE

(mL/hr)


VIALS



15 mcg/m2/day

24 hours

72 hours

96 hours

48 hours

1

2

1

1

1

3

2

10

3.3

2.5

8.47.97.36.86.25.75.14.64

3.42.92.3

1.5 – 1.591.4 – 1.491.3 – 1.391.2 – 1.291.1 – 1.191 – 1.09

0.9 – 0.990.8 – 0.890.7 – 0.790.6 – 0.690.5 – 0.590.4 – 0.49

1.5 – 1.59

1.5 – 1.59

1.4 – 1.49

1.4 – 1.49

1.3 – 1.39

1.3 – 1.39

1.2 – 1.29

1.2 – 1.29

1.1 – 1.19

1.1 – 1.19

1 – 1.09

1 – 1.09

0.9 – 0.99

0.9 – 0.99

0.8 – 0.89

0.8 – 0.89

0.7 – 0.79

0.7 – 0.79

0.6 – 0.69

0.6 – 0.69

0.5 – 0.59

0.5 – 0.59

0.4 – 0.49

0.4 – 0.49

1.5 – 1.591.4 – 1.491.3 – 1.391.2 – 1.291.1 – 1.191 – 1.09

0.9 – 0.990.8 – 0.890.7 – 0.790.6 – 0.690.5 – 0.590.4 – 0.49

2.12

1.81.71.61.41.31.11

0.860.720.59

6.35.95.55.14.74.23.83.43

2.62.21.8

4.23.93.73.43.12.82.62.32

1.71.41.2

5


Use only polyolefi n, PVC di-ethylhexylphthalate-free (DEHP-free), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes and polyolefi n, PVC DEHP-free, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 µm in-line fi lter.

2

3






LIST OF MATERIALS DOSE INFUSION DURATION BSA (m2)

INFUSIONRATE

(mL/hr)


VIALS



Table 2. Materials Required for the Preparation of BLINCYTO Infusion Solution (For Patients Weighing Less Than 45 kg)

5 mcg/m2/day

24 hours

72 hours

96 hours

48 hours 1

1

1

1

10

3.3

2.5

2.82.62.42.32.11.91.71.51.31.2

0.970.78

1.5 – 1.591.4 – 1.491.3 – 1.391.2 – 1.291.1 – 1.191 – 1.09

0.9 – 0.990.8 – 0.890.7 – 0.790.6 – 0.690.5 – 0.590.4 – 0.49

1.5 – 1.59

1.5 – 1.59

1.4 – 1.49

1.4 – 1.49

1.3 – 1.39

1.3 – 1.39

1.2 – 1.29

1.2 – 1.29

1.1 – 1.19

1.1 – 1.19

1 – 1.09

1 – 1.09

0.9 – 0.99

0.9 – 0.99

0.8 – 0.89

0.8 – 0.89

0.7 – 0.79

0.7 – 0.79

0.6 – 0.69

0.6 – 0.69

0.5 – 0.59

0.5 – 0.59

0.4 – 0.49

0.4 – 0.49

1.5 – 1.591.4 – 1.491.3 – 1.391.2 – 1.291.1 – 1.191 – 1.09

0.9 – 0.990.8 – 0.890.7 – 0.790.6 – 0.690.5 – 0.590.4 – 0.49

0.70.660.610.560.520.470.430.380.330.290.240.2

2.12

1.81.71.61.41.31.11

0.860.720.59

1.41.31.21.11

0.940.850.760.670.570.480.39

5


Use only polyolefi n, PVC di-ethylhexylphthalate-free (DEHP-free), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes and polyolefi n, PVC DEHP-free, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 µm in-line fi lter.9 10

IMPORTANT RISK MINIMIZATION INFORMATION FOR NURSESThis educational brochure contains important information regarding the administration of BLINCYTO® (blinatumomab) and the risks of medication errors, cytokine release syndrome (CRS), and neurologic events. This educational material is essential to ensure the safe and eff ective use of the product and appropriate management of the important selected risks and therefore it is advised to be read carefully before administering the medicinal product.

If you have any questions about the administration and the adverse events of BLINCYTO, refer to the Product Information, which is provided with this educational brochure.

Important Information Regarding BLINCYTO

The following actions should be taken to prevent or minimize the risk of medication errors and to provide important counseling information on neurologic events and cytokine release syndrome.

ADMINISTRATION

IV lines

• Do not fl ush the infusion lines into the patient, 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.

• Only program the pump based on the printed infusion rate on the label attached to the infusion bag.

• For the infusion rate ask the consultant pharmacist/doctor. Do not calculate the infusion rate yourself.

• Lock the pump and make sure the battery is adequately charged with each bag change.

• Instruct patients not to unlock the pump.• If the pump does not appear to perform properly (for example:

alarm goes off ) at any time, instruct patients and caregivers not to try to fi x the pump and tell them to get help from the treating physician or from you immediately.

• Instruct patients not to change any pump settings on purpose (with the exception of stopping the pump in case of emergency).

• Remember to check if the remaining volume of infusion bag correlates with the set infusion rate prior to each bag change. If the remaining volume of infusion bag does not correlate with the set infusion rate prior to each bag change, please record discrepancy and contact the physician for further instruction.

• Healthcare professional supervision or hospitalization is recommended in instances where treatment is being re-initiated following an interruption of 4 or more hours (see section 2, Dosage and Administration of the Product Information).

• BLINCYTO solution is a preservative-free solution. Aseptic technique must always be adhered to when administering BLINCYTO.

• Instruct the patients and/or caregivers on how to perform catheter site care as required.

Pump specifi cationsand settings

Therapyinterruption

Catheter site care

STEP 1• Reconstitute each vial of BLINCYTO powder for concentrate with 3 mL of preservative-

free Sterile Water for Injection, by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder (Do not use saline solution, stabilizer solution or any other liquids).

• Gently swirl contents to avoid excess foaming. Do not shake.• Visually inspect the reconstituted solution for particulate matter and to confi rm color.

The solution should be clear to slightly opalescent, colourless to slightly yellow.• Repeat this step according to the required number of BLINCYTO vials as reported in Table

1 or 2 above.

STEP 2• Aseptically add 270 mL 0.9% Sodium Chloride Injection to the IV bag prior to the addition

of IV Solution Stabilizer and reconstituted BLINCYTO.• Add 5.5mL of IV Solution Stabilizer to the IV bag containing 0.9% Sodium Chloride

Injection.• Gently mix the contents of the bag to avoid foaming.• Discard remaining IV Solution Stabilizer vial, if applicable.

STEP 3• According to the desired dose and infusion duration reported in Table 1 or 2 above,

transfer appropriate amount of reconstituted BLINCYTO solution from step 1 into the IV bag containing 0.9% Sodium Chloride Injection and IV Solution Stabilizer from step 2.

• Gently mix the contents of the bag to avoid foaming.

STEP 4• Under aseptic conditions, attach the intravenous tubing to the prepared BLINCYTO

infusion solution bag with the sterile 0.2 μm in-line fi lter.

STEP 5• Remove air from the prepared BLINCYTO infusion solution bag.

STEP 6• Prime the intravenous infusion line with the prepared BLINCYTO infusion solution.• Do not prime the intravenous infusion line with Normal Saline (0.9% Sodium

Chloride) solution for injection.

STEP 7• Store the prepared BLINCYTO infusion solution bag at 2ºC to 8ºC for a maximum of 10

days if not immediately used (for further information, please see section 2.6 Storage Requirements of the Product Information).

Table 3. Steps to prepare BLINCYTO infusion solution under aseptic conditions using aseptic techniques

11 12

COUNSELING

• BLINCYTO has been observed to cause neurological toxicities in approximately 65% of patients. Assess patients for signs and symptoms of neurological events (eg, convulsions, speech disorders, and confusion) prior to and throughout the treatment cycle (see section 5.2 Neurological Toxicities of the Product Information for further information). Consider using a writing test periodically to assist with monitoring for neurological events during BLINCYTO treatment.

• Elderly patients experience a higher rate of neurological events.• Counsel patients on the potential neurologic effects.• Advise patients: • Not to drive, use heavy machinery, or engage in hazardous

activities while receiving BLINCYTO. • To contact you or the doctor if they experience neurological

symptoms.

• Cytokine release syndrome, which may be life-threatening or fatal, has occurred in patients taking BLINCYTO. Patients should be monitored for potential signs and symptoms of CRS or infusion reaction including pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing.

• Counsel patients on the signs or symptoms of potential CRS.• Advise patients to contact you or their doctor if they experience

signs or symptoms associated with CRS or infusion reactions.

Neurologic events

Cytokine release

syndrome (CRS)

This document is not a comprehensive list of Safety events; please refer to the Product Information for BLINCYTO for further information.

This document has been approved by H.S.A. on 18 June 2020

13

For Healthcare Professionals onlyAll images are for illustration purposes only.Please read full prescribing information prior to administration.For further information, please contact Medical Information at 800 616 7094 or email: [email protected]

Amgen Biotechnology Singapore Pte Ltd3 Fraser Street#15-26/27 DUO TowerSingapore 189352

Documents

IMPORTANT RISK MINIMIZATION INFORMATION · Important Information Regarding BLINCYTO The following actions should be taken to prevent or minimize the risk of medication errors and