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A GUIDE FOR MANAGING REBLOZYL THERAPY FOR ANEMIA IN ADULTS WITH β-THALASSEMIA REQUIRING REGULAR RED BLOOD CELL TRANSFUSIONS 1 Please see Important Safety Information continued on page 19 and accompanying full Prescribing Information for REBLOZYL. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thrombosis/Thromboembolism Thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly. REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

Transcript of A GUIDE FOR MANAGING REBLOZYL THERAPY › ... › US-RBZ-19-0160_Nurse_Guide_11.… · A GUIDE FOR...

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A GUIDE FOR MANAGING REBLOZYL THERAPYFOR ANEMIA IN ADULTS WITH β-THALASSEMIA REQUIRING REGULAR RED BLOOD CELL TRANSFUSIONS1

Please see Important Safety Information continued on page 19 and accompanying full Prescribing Information for REBLOZYL.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thrombosis/Thromboembolism Thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

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β-thalassemia

03 Disease overview

05 How REBLOZYL works

REBLOZYL clinical trial06 Phase 3 BELIEVE trial design

07 Baseline characteristics

Safety08 Warnings and precautions

09 Adverse reactions in the clinical trial

11 Discontinuations and dose modifications

Dosing 12 REBLOZYL dosing information

13 REBLOZYL pharmacokinetics (PK)

Reconstitution 14 Reconstituting REBLOZYL

Administration 16 Instructions for subcutaneous (SC) administration

17 Example: How to calculate and deliver a dose

Storage18 Storing REBLOZYL

Important Safety Information (ISI) and Support 19 Important Safety Information

20 Celgene Patient Support®

TABLE OF CONTENTS

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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ASIA

AFRICAMIDDLE

EAST

MEDITERRANEAN

β-thalassemia is seen throughout the world due to modern migration patterns but is most common in the areas shown below2

UNITED STATES

• Thalassemias affect approximately 2000 patients living in the US, with 1000 patients having β-thalassemia major4,5

• The prevalence of thalassemias in the US has increased by 7.5% over the past 5 decades due to immigration

of people from affected regions; however, the exact prevalence in the US is not known6

• Approximately 68,000 people are born with β-thalassemia worldwide each year2

β-THALASSEMIA IS A GENETIC DISORDER2

β-thalassemia is an inherited blood disorder seen throughout the world2

• Approximately 55% are older than 20 years (in a study of 361 patients, mean age 23.2 years, in the Thalassemia Clinical Research Network)3

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• β-thalassemia is triggered by inadequate (β+) or absent (β0) production or synthesis of β subunit of hemoglobin (Hgb) due to mutations in one or more copies of the β-globin gene2,7

• In β-thalassemia, the inadequate amount or absence

of β-globin leads to an imbalance in paired α- and β-globin chains8

β-THALASSEMIA IS CAUSED BY MUTATIONS IN THE β-GLOBIN GENE2

• This imbalance causes an accumulation of erythroid precursors, leading to ineffective erythropoiesis2

• Ineffective erythropoiesis in β-thalassemia is

characterized by increased erythroid proliferation, reduced maturation, and increased death of erythroid precursors, leading to anemia9

Normal adult hemoglobin10

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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• Decreased abnormally elevated Smad2/3 signaling

• Improved hematology parameters associated with ineffective erythropoiesis

How REBLOZYL works is based on preclinical studies in mice1

REBLOZYL IS THE FIRST AND ONLY ERYTHROID MATURATION AGENT1

TGF-β, transforming growth factor beta.

In a model of β-thalassemia, REBLOZYL:

REBLOZYL PROMOTED ERYTHROID MATURATION through differentiation of late-stage erythroid precursors (normoblasts)

• REBLOZYL is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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PIVOTAL PHASE 3 BELIEVE TRIAL DESIGN

REBLOZYL was evaluated in the phase 3, multicenter, randomized, double-blind, placebo-controlled BELIEVE trial of 336 adult patients with β-thalassemia requiring regular RBC transfusions (6–20 RBC units per 24 weeks).1

α-thalassemia, alpha thalassemia; ESA, erythropoiesis-stimulating agent; HbS, hemoglobin S; SC, subcutaneous.

All patients in both arms of the trial were eligible to receive best supportive care (BSC) as needed, including1: • RBC transfusions • Iron-chelating agents • Use of antibiotic, antiviral, and antifungal therapy • Nutritional support

Key inclusion criteria:• Adults ≥18 years of age

• β-thalassemia requiring regular RBC transfusions

- 6–20 RBC units per 24 weeks

- No transfusion-free period >35 days Key exclusion criteria:• HbS/β-thalassemia or α-thalassemia • Patients who had major organ damage (liver, heart, or lung disease, or renal insufficiency)

• Patients with recent deep vein thrombosis or stroke or recent use of ESA, immunosuppressant, or hydroxyurea therapy

REBLOZYL + BSC1

SC every 3 weeks (n = 224) as long as a reduction

in transfusion requirement was observed or until unacceptable toxicity

Placebo + BSC1

SC every 3 weeks(n = 112)

Randomized 2:11

Patient population (N = 336)1

• Starting dose: 1 mg/kg • Patients could have dose

increased to 1.25 mg/kg

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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BASELINE CHARACTERISTICS Baseline disease characteristics of β-thalassemia in BELIEVE1

a Missing category includes patients in the population who had no result for the parameter listed. HbE, hemoglobin E.

Patient population characteristics1

• The median age was 30 years (range, 18–66) • 42% of patients were male • 54.2% of patients were white, 34.8% were Asian, 0.3% were black or African American,

7.7% reported their race as “other,” and 3% were not collected

Disease characteristics REBLOZYL (n = 224)

Placebo(n = 112)

β-thalassemia diagnosis, n (%)

β-thalassemia 174 (77.7) 83 (74.1)

HbE/β-thalassemia 31 (13.8) 21 (18.8)

β-thalassemia combined with α-thalassemia 18 (8) 8 (7.1)

Missinga 1 (0.4) 0

Baseline transfusion burden 12 weeks prior to randomization, units/12 weeks

Median (min, max) 6.12 (3, 14) 6.27 (3, 12)

β-thalassemia gene mutation grouping, n (%)

β0/β0 68 (30.4) 35 (31.3)

Non-β0/β0 155 (69.2) 77 (68.8)

Missinga 1 (0.4) 0

Baseline serum ferritin level, μg/L

N 220 111

Median (min, max) 1441.25 (88, 6400) 1301.50 (136, 6400)

Splenectomy, n (%)

Yes 129 (57.6) 65 (58)

No 95 (42.4) 47 (42)

Age patient started regular transfusions, years

N 169 85

Median (min, max) 2 (0, 52) 2 (0, 51)

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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WARNINGS AND PRECAUTIONS Thrombosis/thromboembolism1

In adult patients with β-thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. Reported TEEs included deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic strokes. Patients with known risk factors for thromboembolism, eg, splenectomy or concomitant use of hormone replacement therapy, may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients with β-thalassemia at increased risk of TEE. Monitor patients receiving REBLOZYL for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension1

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with β-thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) >130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) >80 mm Hg. Monitor blood pressure prior to each administration. Manage new-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-fetal toxicity1 Based on findings from animal reproductive studies, REBLOZYL may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes including increased embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD) of 1.25 mg/kg.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with REBLOZYL and for at least 3 months after the final dose.

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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Adverse reaction

REBLOZYL (n = 223)

Placebo (n = 109)

All Grades

n (%)Grades ≥3a

n (%)All Grades

n (%)Grades ≥3

n (%)

Musculoskeletal and connective tissue disorders

Bone pain 44 (20) 3 (1) 9 (8) 0 (0)

Arthralgia 43 (19) 0 (0) 13 (12) 0 (0)

Infections and infestation

Influenza 19 (9) 0 (0) 6 (6) 0 (0)

Viral upper respiratory infection 14 (6) 1 (0.4) 2 (2) 0 (0)

Nervous system disorders

Headache 58 (26) 1 (<1) 26 (24) 1 (1)

Dizziness 25 (11) 0 (0) 5 (5) 0 (0)

General disorders and administration site conditions

Fatigue 30 (14) 0 (0) 14 (13) 0 (0)

Gastrointestinal disorders

Abdominal painb 31 (14) 0 (0) 13 (12) 0 (0)

Diarrhea 27 (12) 1 (<1) 11 (10) 0 (0)

Nausea 20 (9) 0 (0) 6 (6) 0 (0)

Vascular disorders

Hypertensionc 18 (8) 4 (2) 3 (3) 0 (0)

Metabolism and nutrition disorders

Hyperuricemia 16 (7) 6 (3) 0 (0) 0 (0)

Respiratory, thoracic, and mediastinal disorders

Cough 32 (14) 0 (0) 12 (11) 0 (0)

ADVERSE REACTIONS IN THE CLINICAL TRIAL

aLimited to Grade 3 reactions with the exception of 4 events of Grade 4 hyperuricemia. bGrouped term includes: Abdominal pain and abdominal pain upper. cGrouped term includes: Essential hypertension, hypertension, and hypertensive crisis.

• The data in the Warnings and Precautions reflect exposure to REBLOZYL as a single agent administered across a range of doses (0.125 mg/kg–1.75 mg/kg) in 571 patients in 4 trials1

Adverse drug reactions (>5%) in patients receiving REBLOZYL with a difference between arms of 1% in the BELIEVE trial1

• The median duration of treatment was similar between the REBLOZYL and placebo arms (63.3 weeks vs 62.1 weeks, respectively)1

• Per protocol, patients in both the REBLOZYL and placebo arms were to stay on therapy for at least 48 weeks in the double-blind phase of the trial1

• Among patients receiving REBLOZYL, 94% were exposed for 6 months or longer and 72% were exposed for greater than 1 year1

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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• Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions reported in 1% of patients were cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)1

• The most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26%), bone pain (20%), arthralgia (19%), fatigue (14%), cough (14%), abdominal pain (14%), diarrhea (12%), and dizziness (11%)1

• Clinically relevant adverse reactions in <5% of patients include vertigo/vertigo positional, syncope/presyncope, injection site reactions, and hypersensitivity1

• Of 284 patients with β-thalassemia who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, 4 patients (1.4%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including 2 patients (0.7%) who had neutralizing antibodies

• Luspatercept-aamt serum concentration tended to decrease in the presence of neutralizing antibodies

• There were no severe acute systemic hypersensitivity reactions reported for patients with anti-luspatercept-aamt antibodies in REBLOZYL clinical trials, and there was no association between hypersensitivity type reaction or injection site reaction and presence of anti-luspatercept-aamt antibodies

ADVERSE REACTIONS IN THE CLINICAL TRIAL (CONT'D)

Liver function laboratory abnormalities in the BELIEVE trial1

Immunogenicity1

REBLOZYL(n = 223)

n (%)

Placebo(n = 109)

n (%)

ALT ≥3 × ULN 26 (12) 13 (12)

AST ≥3 × ULN 25 (11) 5 (5)

ALP ≥2 × ULN 17 (8) 1 (<1)

Total bilirubin ≥2 × ULN 143 (64) 51 (47)

Direct bilirubin ≥2 × ULN 13 (6) 4 (4)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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Discontinuations due to adverse reactions1

Permanent discontinuation due to an adverse reaction (Grades 1–4) occurred in 5.4% of patients who received REBLOZYL. Most frequent adverse reactions requiring permanent discontinuation in patients who received REBLOZYL included:

• Arthralgia (1%)

• Back pain (1%)

• Bone pain (<1%) • Headache (<1%)

Dose reductions and interruptions due to adverse reactions1

• Dosage reductions due to an adverse reaction occurred in 2.7% of patients who received REBLOZYL

— Most frequent adverse reactions requiring dosage reduction in >0.5% of patients who received REBLOZYL included hypertension and headache

• Dosage interruptions due to an adverse reaction occurred in 15.2% of patients who received REBLOZYL

— Most frequent adverse reactions requiring dosage interruption in >1% of patients who received REBLOZYL included upper respiratory tract infection, ALT increase, and cough

DISCONTINUATIONS AND DOSE MODIFICATIONS IN THE PHASE 3 BELIEVE CLINICAL TRIAL

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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If no decrease in transfusion burden

after at least 3 consecutive doses (9 weeks) at the maximum dose of 1.25 mg/kg

If no decrease in transfusion burden

after at least 2 consecutive doses (6 weeks) of 1 mg/kg

DOSE 5

3 weeks 3 weeks 3 weeks

CONTINUE* UNLESS UNACCEPTABLE TOXICITY OCCURS

CONTINUE UNLESS UNACCEPTABLE TOXICITY OCCURS

3 weeks

1 mg/kg

START

DOSE 1 DOSE 2 DOSE 3

3 weeks

3 weeks

1 mg/kg

START

DOSE 1 DOSE 2

3 weeks

DOSE 6DOSE 4DOSE 3*

DISCONTINUE 1.25 mg/kg

INCREASE DOSE

Increase dose to maximum of 1.25 mg/kg if no reduction in transfusion burden is seen after at least 2 consecutive doses of 1 mg/kg 3 weeks apart (6 weeks)

Continue treatment as long as reduction in transfusion burden from baseline is observed1

= 1 mg/kg

= 1.25 mg/kg

If a decrease in transfusion burden occurs after at least 2 consecutive doses 3 weeks apart (6 weeks), continue at 1 mg/kg

*A dose increase to 1.25 mg/kg may occur at any time during treatment after patients have received at least 2 consecutive doses of 1 mg/kg.

REBLOZYL DOSING INFORMATION Assess and review Hgb results prior to each administration1 • Start patients at the recommended starting dose of 1 mg/kg by SC injection once every 3 weeks

• If an RBC transfusion occurred prior to dosing, the pretransfusion Hgb level must be considered for dosing purposes

• If the pre-dose Hgb is ≥11.5 g/dL and the Hgb level is not influenced by recent transfusion, delay dosing until the Hgb is ≤11 g/dL

Continuation and discontinuation recommendations1

• If a planned administration of REBLOZYL is delayed or missed, administer REBLOZYL as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses

• Overall, 53% of patients in the BELIEVE trial had their dose increased to 1.25 mg/kg (46% REBLOZYL, n = 223; 66% placebo, n = 109)

• Discontinue REBLOZYL if a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time

• Do not increase the dose beyond the maximum dose of 1.25 mg/kg

Continue treatment as long as reduction in transfusion burden from baseline is observed1

• If a patient experienced a response followed by a lack of or lost response to REBLOZYL, initiate a search for causative factors (eg, a bleeding event)

• If typical causes for a lack or loss of hematologic response are excluded, follow dosing recommendations for management of patients with an insufficient response to REBLOZYL therapy

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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PK1 • REBLOZYL exhibited linear PK over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting

dosage) in patients with β-thalassemia

• The mean (% coefficient of variation [%CV]) steady-state AUC was 126 (35.9%) day•µg/mL at 1 mg/kg and 157 (35.9%) day•µg/mL at 1.25 mg/kg in patients with β-thalassemia

• The mean (%CV) steady-state Cmax was 8.17 (29.9%) µg/mL at 1 mg/kg and 10.2 (29.9%) µg/mL at 1.25 mg/kg in patients with β-thalassemia

• REBLOZYL serum concentration reached steady state after 3 doses when administered every 3 weeks

• The accumulation ratio of REBLOZYL was approximately 1.5

Specific populations1 • No clinically significant differences in the REBLOZYL PK was observed based on:

— Age (18–66 years), sex, or race/ethnicity (Asian, white) — Mild to severe hepatic impairment (total bilirubin ≤ ULN and AST or ALT > ULN, or total bilirubin > ULN and any AST or ALT) — Mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–89 mL/min/1.73 m2) — Baseline albumin (30–56 g/L) — Baseline serum erythropoietin (2.4–972 U/L) — RBC transfusion burden (0–34 units/24 weeks) — β-thalassemia genotype (β0/β0 vs non-β0/β0)

— Splenectomy

• The effect of AST or ALT >3 x ULN and the effect of severe renal impairment (eGFR <29 mL/min/1.73 m2) on REBLOZYL PK is unknown

• The apparent CL/F and Vd /F of REBLOZYL increased with increasing body weight (34–97 kg)

Drug interactions1 • No clinically significant differences in REBLOZYL PK were observed when used concomitantly with

iron-chelating agents

Lactation1 • Luspatercept-aamt was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the

drug will be present in human milk. There are no data on the presence of REBLOZYL in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with REBLOZYL, and for 3 months after the last dose

REBLOZYL PHARMACOKINETICS (PK)

CL/F, clearance; Vd /F, volume of distribution.

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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Reconstitution volumes

Vial sizeAmount of Sterile

Water for Injection, USP required for reconstitution

Final concentration Deliverable volume

25 mg vial 0.68 mL 25 mg/0.5 mL 0.5 mL

75 mg vial 1.6 mL 75 mg/1.5 mL (50 mg/mL) 1.5 mL

RECONSTITUTING REBLOZYL REBLOZYL is available in 2 strengths as single-dose vials for reconstitution1

REBLOZYL should be reconstituted and administered by a healthcare professional1

• Reconstitute REBLOZYL with Sterile Water for Injection, USP only

Important considerations for REBLOZYL reconstitution1

• Reconstitute the number of REBLOZYL vials to achieve the appropriate dose based on the patient's weight • Use a syringe with suitable graduations for reconstitution to ensure accurate dosage

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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RECONSTITUTION INSTRUCTIONS FOR REBLOZYL

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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7. Inspect. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. REBLOZYL is a colorless to slightly yellow, clear to slightly opalescent solution, which is free of foreign particulate matter. Do not use if undissolved product or foreign particulate matter is observed.

6. Repeat. Repeat step 5 seven more times to ensure complete reconstitution of material on the sides of the vial.

4. Inspect. Inspect the vial for undissolved particles in the solution. If undissolved powder is observed, repeat step 3 until the powder is completely dissolved.

1. Add Sterile Water for Injection, USP. Reconstitute with Sterile Water for Injection, USP using volumes described in the reconstitution volumes table on page 14 with the stream directed onto the lyophilized powder. Allow to stand for 1 minute.

2. Discard the needle and syringe used for reconstitution. The needle and syringe used for reconstitution should not be used for SC injections.

3. Mix and wait. Gently swirl the vial in a circular motion for 30 seconds. Stop swirling and let the vial sit in an upright position for 30 seconds.

5. Mix and wait. Invert the vial and gently swirl in an inverted position for 30 seconds. Bring the vial back to the upright position, and let it sit for 30 seconds.

Adhere to the following steps to properly reconstitute REBLOZYL1

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INSTRUCTIONS FOR SC ADMINISTRATION

NOTE: Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. • Do not mix with other medications

Step 1: Verify correct dose

for the patient

• Calculate the exact total dosing volume of 50 mg/mL solution required for the patient

Step 2: Plan and prep for injection

• Slowly withdraw the dosing volume of the reconstituted REBLOZYL solution from the single-dose vial(s) into a syringe

• Divide doses requiring larger reconstituted volumes (ie, >1.2 mL) into separate similar volume injections and inject into separate sites

Step 3: Subcutaneousadministration

• If multiple injections are required, use a new syringe and needle for each SC injection

• Administer the SC injection into the upper arm, thigh, and/or abdomen

Front Back

REBLOZYL is administered subcutaneously and is available in 2 vial sizes (25 mg and 75 mg)1

• Prior to injection, allow solution to reach room temperature for a more comfortable injection

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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REBLOZYL should be reconstituted and administered by a healthcare professional1

Sample calculation for SC administration of REBLOZYL

Doses with reconstituted volumes larger than 1.2 mL should be divided into separate, similar-volume syringes for injection and injected into separate sites (upper arm, thigh, and/or abdomen) Injection 1: 0.89 mL – upper arm Injection 2: 0.89 mL – thigh or abdomen

• Average adult male aged 30 years and weighing 197 pounds (89 kg) • 1 mg of REBLOZYL per 1 kg = 89 mg starting dose

EXAMPLE: HOW TO CALCULATE AND DELIVER A DOSE

Total volume of reconstituted 50 mg/mL solution needed to administer 89 mg: 1.78 mL

Number of vials REBLOZYL Concentration

after reconstitutionSolution needed

for administrationMilligrams in solution

1 75 mg vial 75 mg/1.5 mL (50 mg/mL) Use 1.5 mL 75 mg

1 25 mg vial 25 mg/0.5 mL Use 0.28 mL 14 mg

Total volume needed 1.78 mL 89 mg

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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STORING REBLOZYL

REBLOZYL requires cold storage1

STORAGE OF UNRECONSTITUTED VIAL

• Store unreconstituted vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light

• Do not freeze

STORAGE OF RECONSTITUTED SOLUTION

• If the reconstituted solution is not used immediately, store at room temperature at 20°C to 25°C (68°F to 77°F) in the original vial for up to 8 hours. Discard if not used within 8 hours of reconstitution

• Alternatively, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours in the original vial

— Remove from refrigerated condition 15 to 30 minutes prior to injection to allow solution to reach room temperature for a more comfortable injection

— Discard if not used within 24 hours of reconstitution

• Do not freeze the reconstituted solution

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism Thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) >130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) >80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose.

ADVERSE REACTIONS Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML).

Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%).

LACTATION It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see accompanying full Prescribing Information for REBLOZYL.

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For more information

CELGENE PATIENT SUPPORT®

Celgene Patient Support® provides• A single Specialist assigned to help patients in your geographic area

• A Field Reimbursement Specialist in each region with information on payer policies, billing, and coding for REBLOZYL

• Assistance with understanding patient insurance coverage for REBLOZYL

• Information about financial assistance for REBLOZYL

Financial assistance

There are programs and organizations that may help pay for REBLOZYL, depending on a patient’s insurance situation:

Celgene Commercial Co-pay Program Co-pay responsibility for REBLOZYL is reduced to $0 (subject to annual benefit limits) for eligible patients with commercial or private insurance (including healthcare exchanges).*

Celgene Patient Assistance Program (PAP) REBLOZYL may be available at no cost for qualified patients who are uninsured or underinsured.†

Independent third-party organizations Patients who are unable to afford their medication (including patients with Medicare, Medicaid, or other government-sponsored insurance) may be able to receive help from independent third-party organizations.‡

Insurance-related assistance

Our Specialists are available to assist with each of the following steps in the insurance approval process for REBLOZYL§:

• Benefits investigation

• Prior authorization/precertification assistance¶

Visit us at www.celgenepatientsupport.com

Call us at 1-800-931-8691,Monday – Friday, 8 am – 8 pm ET(translation services available)

*Other eligibility requirements and restrictions apply. Please see full Terms and Conditions on the Celgene Patient Support® website.† Patients must meet specified financial and insurance eligibility requirements to qualify for assistance. Please see Eligibility Requirements on the Celgene Patient Support® website.

‡Financial and medical eligibility requirements vary by organization.§Celgene cannot provide insurance advice or make insurance decisions.¶ Celgene provides a facilitation service and will not provide any medical input into a prior authorization or an appeal.

Email us [email protected] fax to 1-800-822-2496

• Appeals assistance¶

• Educating patients about insurance coverage or other programs for which they may qualify

Enrolling in Celgene Patient Support®

Please see Important Safety Information on page 19 and accompanying full Prescribing Information for REBLOZYL.

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References: 1. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2019. 2. Origa R. β-Thalassemia. Genet Med. 2017;19(6):609-619. 3. Vogiatzi MG, Macklin EA, Trachtenberg FL, et al. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. Br J Haematol. 2009;146(5):546-556. 4. World Health Organization, Thalassaemia International Federation. Management of haemoglobin disorders: report of a joint WHO-TIF meeting. November 16-18, 2007; Nicosia, Cyprus. 5. The Centers for Disease Control and Prevention. Thalassemia awareness. CDC website. https://www.cdc.gov/features/international-thalassemia/index.html. Accessed October 8, 2019. 6. Sayani FA, Kwiatkowski JL. Increasing prevalence of thalassemia in America: implications for primary care. Ann Med. 2015;47(7):592-604. 7. Cappellini MD, Porter JB, Viprakasit V, Taher AT. A paradigm shift on beta-thalassaemia treatment: how will we manage this old disease with new therapies? Blood Rev. 2018;32(4):300-311. 8. Ribeil JA, Arlet JB, Dussiot M, Moura IC, Courtois G, Hermine O. Ineffective erythropoiesis in β-thalassemia. ScientificWorldJournal. 2013;2013;394295. 9. Oikonomidou PR, Rivella S. What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev. 2018;32(2):130-143. 10. Bringas M, Petruk AA, Estrin DA, Capece L, Martí MA. Tertiary and quaternary structural basis of oxygen affinity in human hemoglobin as revealed by multiscale simulations. Sci Rep. 2017;7(1):10926.

REBLOZYL® and Celgene Patient Support® are registered trademarks of Celgene Corporation. REBLOZYL® is licensed from Acceleron Pharma Inc. © 2019 Celgene Corporation 11/19 US-RBZ-19-0160

LEARN MORE ABOUT REBLOZYL

Visit REBLOZYLpro.com for additional and future resources for you and your patients

REBLOZYL dosing guide

Patient brochure

Dosing and reconstitution videos

Please see accompanying full Prescribing Information for REBLOZYL.