label

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

REVLIMID

®

safely and effectively. See full prescribing information for

REVLIMID.

REVLIMID (lenalidomide) capsules, for oral use

Initial U.S. Approval: 2005

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC

TOXICITY, and VENOUS and ARTERIAL

THROMBOEMBOLISM

See full prescribing information for complete boxed warning.

EMBRYO-FETAL TOXICITY

 Lenalidomide, a thalidomide analogue, caused limb

abnormalities in a developmental monkey study similar to birth

defects caused by thalidomide in humans. If lenalidomide is used

during pregnancy, it may cause birth defects or embryo-fetal

death.

 Pregnancy must be excluded before start of treatment. Prevent

pregnancy during treatment by the use of two reliable methods

of contraception (5.1).

REVLIMID is available only through a restricted distribution

program, called the REVLIMID REMS

®

program (5.2, 17).

HEMATOLOGIC TOXICITY. REVLIMID can cause significant

neutropenia and thrombocytopenia (5.3).

VENOUS AND ARTERIAL THROMBOEMBOLISM

 Significantly increased risk of deep vein thrombosis (DVT) and

pulmonary embolism (PE), as well as risk of myocardial

infarction and stroke in patients with multiple myeloma

receiving REVLIMID with dexamethasone. Anti-thrombotic

prophylaxis is recommended (5.4).

--------------------------RECENT MAJOR CHANGES----------------------------

Indications and Usage, Follicular Lymphoma (1.4) 5/19

Indications and Usage, Marginal Zone Lymphoma (1.5) 5/19

Dosage and Administration (2.4, 2.5) 5/19

---------------------------INDICATIONS AND USAGE----------------------------

REVLIMID is a thalidomide analogue indicated for the treatment of adult

patients with:

 Multiple myeloma (MM), in combination with dexamethasone (1.1).

 MM, as maintenance following autologous hematopoietic stem cell

transplantation (auto-HSCT) (1.1).

 Transfusion-dependent anemia due to low- or intermediate-1-risk

myelodysplastic syndromes (MDS) associated with a deletion 5q

abnormality with or without additional cytogenetic abnormalities (1.2).

 Mantle cell lymphoma (MCL) whose disease has relapsed or progressed

after two prior therapies, one of which included bortezomib (1.3).

 Previously treated follicular lymphoma (FL), in combination with a

rituximab product (1.4).

 Previously treated marginal zone lymphoma (MZL), in combination

with a rituximab product (1.5).

Limitations of Use:

 REVLIMID is not indicated and is not recommended for the treatment

of patients with chronic lymphocytic leukemia (CLL) outside of

controlled clinical trials (1.4).

-----------------------DOSAGE AND ADMINISTRATION-----------------------

 MM combination therapy: 25 mg once daily orally on Days 1-21 of

repeated 28-day cycles. (2.1).

 MM maintenance therapy following auto-HSCT: 10 mg once daily

continuously on Days 1-28 of repeated 28-day cycles (2.1).

 MDS: 10 mg once daily (2.2).

 MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles

(2.3).

 FL or MZL: 20 mg once daily orally on Days 1-21 of repeated 28-day

cycles for up to 12 cycles (2.4).

 Renal impairment: Adjust starting dose based on the creatinine

clearance value (2.5).

 For concomitant therapy doses, see Full Prescribing Information (2.1,

2.4, 14.1, 14.4).

----------------------DOSAGE FORMS AND STRENGTHS---------------------

Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg (3).

-------------------------------CONTRAINDICATIONS------------------------------

 Pregnancy (Boxed Warning, 4.1, 5.1, 8.1).

 Demonstrated severe hypersensitivity to lenalidomide (4.2, 5.9).

-----------------------WARNINGS AND PRECAUTIONS-----------------------

 Increased mortality: serious and fatal cardiac adverse reactions occurred

in patients with CLL treated with REVLIMID (5.5).

 Second Primary Malignancies (SPM): Higher incidences of SPM were

observed in controlled trials of patients with MM receiving REVLIMID

(5.6).

 Increased Mortality: Observed in patients with MM when

pembrolizumab was added to dexamethasone and a thalidomide

analogue (5.7).

 Hepatotoxicity: Hepatic failure including fatalities; monitor liver

function. Stop REVLIMID and evaluate if hepatotoxicity is suspected

(5.8).

 Cutaneous Reactions, including fatalities: Hypersensitivity, angioedema,

Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction

with eosinophilia and systemic symptoms; discontinue REVLIMID if

reactions are suspected. Do not resume REVLIMID if these reactions are

verified (5.9).

 Tumor lysis syndrome (TLS) including fatalities: Monitor patients at

risk of TLS (i.e., those with high tumor burden) and take appropriate

precautions (5.10).

 Tumor flare reaction: Serious tumor flare reactions have occurred

during investigational use of REVLIMID for chronic lymphocytic

leukemia and lymphoma (5.11).

 Impaired Stem Cell mobilization: A decrease in the number of CD34+

cells collected after treatment (> 4 cycles) with REVLIMID has been

reported. Consider early referral to transplant center (5.12).

 Early mortality in MCL: Higher rate of early deaths have occurred in

patients with MCL (5.14).

-------------------------------ADVERSE REACTIONS------------------------------

 MM: Most common adverse reactions (≥20%) include diarrhea, fatigue,

anemia, constipation, neutropenia, leukopenia, peripheral edema,

insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea,

asthenia, pyrexia, upper respiratory tract infection, bronchitis,

nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness,

decreased appetite, thrombocytopenia, and tremor (6.1).

 MDS: Most common adverse reactions (>15%) include

thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue,

constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain,

peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea,

pharyngitis, and epistaxis (6.1).

 Non-Hodgkin’s Lymphoma (NHL: MCL, FL or MZL): Most common

adverse reactions (≥

15%) included neutropenia, thrombocytopenia,

anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia,

cough, upper respiratory tract infection, and rash (6.1).

To report SUSPECTED ADVERSE REACTIONS contact Celgene

Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

-------------------------------DRUG INTERACTIONS------------------------------

 Digoxin: Monitor digoxin plasma levels periodically due to increased

C

max

and AUC with concomitant REVLIMID therapy (7.1).

 Concomitant use of erythropoietin stimulating agents or estrogen

containing therapies with REVLIMID may increase the risk of

thrombosis (7.2).

--------------------------USE IN SPECIFIC POPULATIONS---------------------

 Lactation: Advise not to breastfeed (8.2).

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide

Revised: 5/2019

Reference ID: 4439576

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC

TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

1.2 Myelodysplastic Syndromes

1.3 Mantle Cell Lymphoma

1.4 Follicular Lymphoma

1.5 Marginal Zone Lymphoma

1.6 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Multiple Myeloma

2.2 Recommended Dosage for Myelodysplastic Syndromes

2.3 Recommended Dosage for Mantle Cell Lymphoma

2.4 Recommended Dosage for Follicular Lymphoma or Marginal Zone

Lymphoma

2.5 Recommended Dosage for Patients with Renal Impairment

2.6 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Pregnancy

4.2 Severe Hypersensitivity Reactions

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

5.2 REVLIMID REMS Program

5.3 Hematologic Toxicity

5.4 Venous and Arterial Thromboembolism

5.5 Increased Mortality in Patients with CLL

5.6 Second Primary Malignancies

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is

Added to a Thalidomide Analogue and Dexamethasone

5.8 Hepatotoxicity

5.9 Severe Cutaneous Reactions Including Hypersensitivity Reactions

5.10 Tumor Lysis Syndrome

5.11 Tumor Flare Reaction

5.12 Impaired Stem Cell Mobilization

5.13 Thyroid Disorders

5.14 Early Mortality in Patients with MCL

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Digoxin

7.2 Concomitant Therapies That May Increase the Risk of Thrombosis

7.3 Warfarin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 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 Multiple Myeloma

14.2 Myelodysplastic Syndromes (MDS) with a Deletion 5q

Cytogenetic Abnormality

14.3 Mantle Cell Lymphoma

14.4 Follicular and Marginal Zone Lymphoma

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

16.3 Handling and Disposal

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not

listed.

Reference ID: 4439576

2

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

FULL PRESCRIBING INFORMATION

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental

monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used

during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy

tests before starting REVLIMID

®

treatment. Females of reproductive potential must use 2 forms of contraception or continuously

abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication

Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program,

the REVLIMID REMS

®

program (5.2).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s

toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes

had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction.

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic

syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter.

Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see

Dosage and Administration (2.2)].

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as

risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone

therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical

care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and

the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

REVLIMID in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma (MM).

REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

1.2 Myelodysplastic Syndromes

REVLIMID is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS)

associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

1.3 Mantle Cell Lymphoma

REVLIMID is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of

which included bortezomib.

1.4 Follicular Lymphoma

REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL).

1.5 Marginal Zone Lymphoma

REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL).

1.6 Limitations of Use

REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Multiple Myeloma

REVLIMID Combination Therapy

The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to

Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced [see Clinical Studies

(14.1)]. Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible,

hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.12)].

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4

toxicity judged to be related to REVLIMID.

Table 1: Dose Adjustments for Hematologic Toxicities for MM

Reference ID: 4439576

3

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Platelet counts

Thrombocytopenia in MM

When Platelets Recommended Course

Days 1-21 of repeated 28-day cycle

Fall below 30,000/mcL Interrupt REVLIMID treatment, follow CBC weekly

Return to at least 30,000/mcL Resume REVLIMID at next lower dose. Do not dose

b

elow 2.5 mg daily

For each subsequent drop below 30,000/mcL Interrupt REVLIMID treatmen

t

Return to at least 30,000/mcL Resume REVLIMID at next lower dose. Do not dose

b

elow 2.5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils Recommended Course

Days 1-21 of repeated 28-day cycle

Fall below 1000/mcL Interrupt REVLIMID treatment, follow CBC

weekly

Return to at least 1,000/mcL and neutropenia is the only toxicity Resume REVLIMID at 25 mg daily or initial

starting dose

Return to at least 1,000/mcL and if other toxicity Resume REVLIMID at next lower dose. Do not

dose below 2.5 mg daily

For each subsequent drop below 1,000/mcL Interrupt REVLIMID treatmen

t

Return to at least 1,000/mcL Resume REVLIMID at next lower dose. Do not

dose below 2.5 mg daily

REVLIMID Maintenance Therapy Following Auto-HSCT

Following auto-HSCT, initiate REVLIMID maintenance therapy after adequate hematologic recovery (ANC at least 1000/mcL and/or platelet counts at least

75,000/mcL). The recommended starting dose of REVLIMID is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or

unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 2 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4

toxicity judged to be related to REVLIMID.

Table 2: Dose Adjustments for Hematologic Toxicities for MM

Platelet counts

Thrombocytopenia in MM

When Platelets Recommended Course

Fall below 30,000/mcL

Return to at least 30,000/mcL

If at the 5 mg daily dose,

For a subsequent drop below 30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly

Resume REVLIMID at next lower dose, continuously

for Days 1-28 of repeated 28-day cycle

Interrupt REVLIMID treatment. Do not dose below 5

mg daily for Day 1 to 21 of 28 day cycle

Return to at least 30,000/mcL

Absolute Neutrophil counts (ANC)

Resume REVLIMID at 5 mg daily for Days 1 to 21of

28-day cycle. Do not dose below 5 mg daily for Day 1

to 21 of 28 day cycle

Neutropenia in MM

When Neutrophils

Fall below 500/mcL

Return to at least 500/mcL

If at 5 mg daily dose,

For a subsequent drop below 500/mcL

Recommended Course

Interrupt REVLIMID treatment, follow CBC weekly

Resume REVLIMID at next lower dose,

continuously for Days 1-28 of repeated 28-day cycle

Interrupt REVLIMID treatment. Do not dose below 5

mg daily for Days 1 to 21 of 28-day cycle

Return to at least 500/mcL Resume REVLIMID at 5 mg daily for Days 1 to 21 of

28-day cycle. Do not dose below 5 mg daily for Days

1 to 21 of 28-day cycle

Other Toxicities in MM

For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has

resolved to Grade 2 or lower.

Starting Dose Adjustment for Renal Impairment in MM

[see Dosage and Administration (2.5)].

Recommended Dosage for Myelodysplastic Syndromes

Reference ID: 4439576

4

2.2

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment

until disease progression or unacceptable toxicity.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Platelet counts

If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline is at least 100,000/mcL

When Platelets Recommended Course

Fall below 50,000/mcL Interrupt REVLIMID treatmen

t

Return to at least 50,000/mcL Resume REVLIMID at 5 mg daily

If baseline is below 100,000/mcL

When Platelets Recommended Course

Fall to 50% of the baseline value Interrupt REVLIMID treatmen

t

If baseline is at least 60,000/mcL and Resume REVLIMID at 5 mg daily

returns to at least 50,000/mcL

If baseline is below 60,000/mcL and Resume REVLIMID at 5 mg daily

returns to at least 30,000/mcL

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets Recommended Course

Fall below 30,000/mcL or below 50,000/mcL Interrupt REVLIMID treatment

with platelet transfusions

Return to at least 30,000/mcL Resume REVLIMID at 5 mg daily

(without hemostatic failure)

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets Recommended Course

Fall below 30,000/mcL or below 50,000/mcL Interrupt REVLIMID treatment

with platelet transfusions

Return to at least 30,000/mcL Resume REVLIMID at 2.5 mg daily

(without hemostatic failure)

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:

Absolute Neutrophil counts (ANC)

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ANC is at least 1,000/mcL

When Neutrophils Recommended Course

Fall below 750/mcL Interrupt REVLIMID treatmen

t

Return to at least 1,000/mcL Resume REVLIMID at 5 mg daily

If baseline ANC is below 1,000/mcL

When Neutrophils Recommended Course

Fall below 500/mcL Interrupt REVLIMID treatmen

t

Return to at least 500/mcL Resume REVLIMID at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Neutrophils Recommended Course

Fall below 500/mcL for at least 7 days or below 500/mcL Interrupt REVLIMID treatment

associated with fever (at least 38.5°C)

Return to at least 500/mcL Resume REVLIMID at 5 mg daily

Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils Recommended Course

Fall below 500/mcL for at least 7 days or below 500/mcL Interrupt REVLIMID treatment

associated with fever (at least 38.5°C)

Return to at least 500/mcL Resume REVLIMID at 2.5 mg daily

Reference ID: 4439576

5

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

2.3

2.4

Other Grade 3 / 4 Toxicities in MDS

For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has

resolved to Grade 2 or lower.

Starting Dose Adjustment for Renal Impairment in MDS

[see Dosage and Administration (2.5)].

Recommended Dosage for Mantle Cell Lymphoma

The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma.

Treatment should be continued until disease progression or unacceptable toxicity.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MCL Treatment

Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities

considered to be related to REVLIMID.

Platelet counts

Thrombocytopenia during treatment in MCL

When Platelets

Fall below 50,000/mcL

Recommended Course

Interrupt REVLIMID treatment and follow CBC weekly

Return to at least 50,000/mcL

Resume REVLIMID at 5 mg less than the previous dose. Do

not dose

b

elow 5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in MCL

When Neutrophils

Fall below 1000/mcL for at least 7 days

OR

Falls below 1,000/mcL with an associated temperature at least

38.5°C

OR

Falls

b

elow 500/mcL

Recommended Course

Interrupt REVLIMID treatment and follow CBC weekly

Return to at least 1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do

not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MCL

For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has

resolved to Grade 2 or lower.

Starting Dose Adjustment for Renal Impairment in MCL

[see Dosage and Administration (2.5)].

Recommended Dosage for Follicular Lymphoma or Marginal Zone Lymphoma

The recommended starting dose of REVLIMID is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with

a rituximab-product. Refer to Section 14.4 for specific rituximab dosing from the AUGMENT trial. For dose adjustments due to toxicity with rituximab, refer to the

product prescribing information.

Dose Adjustments for Hematologic Toxicities during FL or MZL Treatment

Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged

to be related to REVLIMID.

Platelet counts

Thrombocytopenia during treatment in FL or MZL

When Platelets

Fall below 50,000/mcL

Return to at least 50,000/mcL

Recommended Course

Interrupt REVLIMID treatment and follow CBC weekly.

If patient starting dose was 20 mg daily, resume REVLIMID

at 5 mg less than the previous dose. Do not dose below 5 mg

daily.

If patient starting dose was 10 mg daily, resume at 5 mg less

than previous dose. Do not dose below 2.5 mg daily.

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in FL or MZL

6

Reference ID: 4439576

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

2.5

When Neutrophils Recommended Course

Fall below 1,000/mcL for at least 7 days Interrupt REVLIMID treatment and follow CBC weekly.

OR

Falls below 1,000/mcL with an associated temperature at least

38.5°C

OR

Falls below 500 /mcL

Return to at least 1,000/mcL If patient starting dose was 20 mg daily, resume REVLIMID

at 5 mg less than the previous dose. Do not dose below 5 mg

daily.

If patient starting dose was 10 mg daily, resume at 5 mg less

than previous dose. Do not dose below 2.5 mg daily.

Other Grade 3 / 4 Toxicities in FL or MZL

For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has

resolved to Grade 2 or below.

Starting Dose Adjustment for Renal Impairment in FL or MZL

[see Dosage and Administration (2.5)].

Recommended Dosage for Patients with Renal Impairment

The recommendations for dosing patients with renal impairment are shown in the following table [see Clinical Pharmacology (12.3)].

Table 3: Dose Adjustments for Patients with Renal Impairment

Renal Function

(Cockcroft-Gault)

Dose in REVLIMID Combination

Therapy for MM and MCL

Dose in REVLIMID Combination

Therapy for FL and MZL

Dose in REVLIMID Maintenance

Therapy Following Auto-HSCT for

MM and for MDS

CLcr 30 to 60 mL/min 10 mg once daily 10 mg once daily 5 mg once daily

CLcr below 30 mL/min (not requiring

dialysis)

15 mg every other day 5 mg once daily 2.5 mg once daily

CLcr below 30 mL/min (requiring

dialysis)

5 mg once daily. On dialysis days,

administer the dose following

dialysis.

5 mg once daily. On dialysis days,

administer the dose following

dialysis.

2.5 mg once daily. On dialysis days,

administer the dose following

dialysis.

REVLIMID Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of

lenalidomide without dose-limiting toxicity.

REVLIMID Maintenance Therapy Following Auto-HSCT for MM and for MCL and MDS: Base subsequent REVLIMID dose increase or decrease on individual

patient treatment tolerance [see Dosage and Administration (2.1- 2.3)].

REVLIMID Combination Therapy for FL or for MZL: For patients with CLcr of 30 to 60 mL/min, after 2 cycles, the REVLIMID dose may be increased to 15 mg

orally if the patient has tolerated therapy.

2.6 Administration

Advise patients to take REVLIMID orally at about the same time each day, either with or without food. Advise patients to swallow REVLIMID capsules whole with

water and not to open, break, or chew them.

3 DOSAGE FORMS AND STRENGTHS

Capsules:

 2.5 mg, white and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink

 5 mg, white opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink

 10 mg, blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink

 15 mg, powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink

 20 mg, powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink

 25 mg, white opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink

4 CONTRAINDICATIONS

4.1 Pregnancy

REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with

lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural

similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during

pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus [see Warnings and Precautions (5.1,

5.2), Use in Special Populations (8.1, 8.3)].

Reference ID: 4439576

7

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

4.2 Severe Hypersensitivity Reactions

REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to

lenalidomide [see Warnings and Precautions (5.8)].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human

birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced

malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to

thalidomide during pregnancy.

REVLIMID is only available through the REVLIMID REMS program [see Warnings and Precautions (5.2)].

Females of Reproductive Potential

Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at

least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to

initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours

prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in

females with irregular menstrual cycles [see Use in Specific Populations (8.3)].

Males

Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with

females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.3)].

Blood Donation

Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant

female patient whose fetus must not be exposed to REVLIMID.

5.2 REVLIMID REMS Program

Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and

Mitigation Strategy (REMS), the REVLIMID REMS program.

Required components of the REVLIMID REMS program include the following:

 Prescribers must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements.

 Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not

pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] and males must comply with contraception

requirements [see Use in Specific Populations (8.3)].

 Pharmacies must be certified with the REVLIMID REMS program, must only dispense to patients who are authorized to receive REVLIMID and comply with

REMS requirements.

Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

Reference ID: 4439576

8

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

5.3 Hematologic Toxicity

REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding

or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts

assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)].

Monitor complete blood counts (CBC) in patients taking REVLIMID in combination with dexamethasone or as REVLIMID maintenance therapy for MM every 7 days

(weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see

Dosage and Administration (2.1)]. In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of REVLIMID-treated patients and

Grade 3 or 4 thrombocytopenia in up to 38% of REVLIMID-treated patients [see Adverse Reactions (6.1)].

Monitor complete blood counts (CBC) in patients taking REVLIMID for MDS weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic

toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days

(range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4

thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed

Warning and Dosage and Administration (2.2)].

Monitor complete blood counts (CBC) in patients taking REVLIMID for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly

thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4

thrombocytopenia was reported in 28% of the patients.

Monitor complete blood counts (CBC) in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-

4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the AUGMENT and MAGNIFY trials, Grade 3 or 4 neutropenia was

reported in 50% and 33%, respectively, of patients in the REVLIMID/rituximab arm. Grade 3 or 4 thrombocytopenia was reported in 2% and 8%, respectively, of

patients in the REVLIMID/rituximab arm [see Adverse Reactions (6.1)].

5.4 Venous and Arterial Thromboembolism

Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with

REVLIMID.

A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with REVLIMID and

dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant

therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious

adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar

between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with REVLIMID and

dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction

(including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of

serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)].

Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g.

hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic

events) occurred in patients with refractory and relapsed MM who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated

with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all pati

ents received antithrombotic

prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The

median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms.

In the AUGMENT trial, the incidence of VTE (including DVT and PE) in FL or MZL patients was 3.4% in the REVLIMID/rituximab arm [see Adverse Reactions

(6.1)]. In the AUGMENT trial, the incidence of ATE (including MI) in FL or MZL patients was 0.6% in the REVLIMID/rituximab arm [see Adverse Reactions (6.1)].

Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to

report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be

based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)].

5.5 Increased Mortality in Patients with CLL

In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the

risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to

18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in

the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment

arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

5.6 Second Primary Malignancies

In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor second primary malignancies (SPM) notably AML and MDS

have been observed. An increase in hematologic SPM including AML and MDS occurred in 5.3% of patients with NDMM receiving REVLIMID in combination with

oral melphalan compared with 1.3% of patients receiving melphalan without REVLIMID. The frequency of AML and MDS cases in patients with NDMM treated with

REVLIMID in combination with dexamethasone without melphalan was 0.4%.

In patients receiving REVLIMID maintenance therapy following high dose intravenous melphalan and auto-HSCT, hematologic SPM occurred in 7.5% of patients

compared to 3.3% in patients receiving placebo. The incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM

was 14.9%, compared to 8.8% in patients receiving placebo with a median follow-up of 91.5 months. Non-melanoma skin cancer SPM, including squamous cell

carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving REVLIMID maintenance, compared to 2.6% in the placebo arm.

Reference ID: 4439576

9

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

In patients with relapsed or refractory MM treated with REVLIMID/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell

carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell

carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving REVLIMID/dexamethasone, compared to 0.6% in the dexamethasone alone arm.

Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed

duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of

REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID.

In the AUGMENT trial with FL or MZL patients receiving REVLIMID/rituximab therapy, hematologic plus solid tumor SPMs, notably AML, have been observed. In

the AUGMENT trial, hematologic SPM of AML occurred in 0.6% of patients with FL or MZL receiving REVLIMID/rituximab therapy. The incidence of hematologic

plus solid tumor SPMs (excluding nonmelanoma skin cancers) was 1.7% in the REVLIMID/rituximab arm with a median follow-up of 29.8 months (range 0.5 to 51.3

months) [see Adverse Reactions (6.1)]. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of

REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID.

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or

PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a

thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.8 Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dexamethasone. In clinical trials, 15% of patients

experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious

hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant

medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a

lower dose may be considered.

5.9 Severe Cutaneous Reactions Including Hypersensitivity Reactions

Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and

systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or

lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior

history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for

Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected and should not

be resumed following discontinuation for these reactions.

5.10 Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with REVLIMID. The patients at risk of TLS a

re those with high tumor burden

prior to treatment. Monitor patients at risk closely and take appropriate preventive approaches. In the AUGMENT trial in FL or MZL patients, TLS occurred in 2

patients (1.1%) in the REVLIMID/rituximab arm. TLS occurred in 1 patient (0.5%) in the MAGNIFY trial during the REVLIMID/rituximab induction period; the

event was a serious, Grade 3 adverse reaction.

5.11 Tumor Flare Reaction

Tumor flare reaction (TFR) has occurred during investigational use of REVLIMID for CLL and lymphoma, and is characterized by tender lymph node swelling, low

grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare reaction may mimic progression of disease (PD).

In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in Cycle 1 and one patient developed

TFR again in Cycle 11. In the AUGMENT trial in FL or MZL patients, TFR was reported in 19/176 (10.8%) of patients in REVLIMID with rituximab arm; one patient

in the REVLIMID/rituximabarm experienced a Grade 3 TFR. In the MAGNIFY trial, 9/222 (4.1%) of patients experienced TFR; all reports were Grade 1 or 2 in

severity and 1 event was considered as serious.

REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR

may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients

with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for

management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

5.12 Impaired Stem Cell Mobilization

A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are auto-HSCT candidates, referral

to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-

containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-

CSF with a CXCR4 inhibitor may be considered.

5.13 Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been reported [see Adverse Reactions (6.2)]. Measure thyroid function before start of REVLIMID treatment and

during therapy.

5.14 Early Mortality in Patients with MCL

In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. On exploratory

multivariate analysis, risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥ 10 x 10

9

/L).

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:

o Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]

10

Reference ID: 4439576

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

6.1

o Hematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)]

o Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]

o Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)]

o Second Primary Malignancies [see Warnings and Precautions (5.6)]

o Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

[see Warnings and Precautions (5.7)]

o Hepatotoxicity [see Warnings and Precautions (5.8)]

o Severe Cutaneous Reactions Including Hypersensitivity Reactions [see Warnings and Precautions (5.9)]

o Tumor Lysis Syndrome [see Warnings and Precautions (5.10)]

o Tumor Flare Reactions [see Warnings and Precautions (5.11)]

o Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12)]

o Thyroid Disorders [see Warnings and Precautions (5.13)]

o Early Mortality in Patients with MCL [see Warnings and Precautions (5.14)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates

in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed MM – REVLIMID Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different

durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received

melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous

arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation,

peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia,

thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest

frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection

in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to

the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were

hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse

reactions leading to discontinuation of REVLIMID were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or

remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6%

by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms*

Body System

Adverse Reaction

All Adverse Reactions

a

Grade 3/4 Adverse Reactions

b

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

General disorders and administration site conditions

Fatigue

%

173 (33) 177 (33) 154 (28) 39 ( 7) 46 ( 9) 31 ( 6)

Asthenia 150 (28) 123 (23) 124 (23) 41 ( 8) 33 ( 6) 32 ( 6)

Pyrexia

c

114 (21) 102 (19) 76 (14)

13 ( 2) 7 ( 1) 7 ( 1)

Non-cardiac chest pain

f

29 ( 5) 31 ( 6) 18 ( 3) <1% < 1% < 1%

Gastrointestinal disorders

Diarrhea 242 (45) 208 (39) 89 (16) 21 ( 4) 18 ( 3) 8 ( 1)

Abdominal pain

% f

109 (20) 78 (14) 60 (11) 7 ( 1) 9 ( 2) < 1%

Dyspepsia

f

57 (11) 28 ( 5) 36 ( 7) <1% < 1% 0 ( 0)

Musculoskeletal and connective tissue disorders

Back pain

c

170 (32) 145 (27) 116 (21) 37 ( 7) 34 ( 6) 28 ( 5)

Muscle spasms

f

109 (20) 102 (19) 61 (11) < 1% < 1% < 1%

Arthralgia

f

101 (19) 71 (13) 66 (12) 9 ( 2) 8 ( 1) 8 ( 1)

Bone pain

f

87 (16) 77 (14) 62 (11) 16 ( 3) 15 ( 3) 14 ( 3)

Pain in extremity

f

79 (15) 66 (12) 61 (11) 8 ( 2) 8 ( 1) 7 ( 1)

Musculoskeletal pain

f

67 (13) 59 (11) 36 ( 7) < 1% < 1% < 1%

Musculoskeletal chest pain

f

60 (11) 51 ( 9) 39 ( 7) 6 ( 1) < 1% < 1%

Muscular weakness

f

43 ( 8) 35 ( 6) 29 ( 5) < 1% 8 ( 1) < 1%

Neck pain

f

40 ( 8) 19 ( 4) 10 ( 2) < 1% < 1% < 1%

Reference ID: 4439576

11

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

All Adverse Reactions

a

Grade 3/4 Adverse Reactions

b

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

Infections and infestations

Bronchitis

c

90 (17) 59 (11) 43 ( 8) 9 ( 2) 6 ( 1) < 1%

Nasopharyngitis

f

80 (15) 54 (10) 33 ( 6) 0 ( 0) 0 ( 0) 0 ( 0)

Urinary tract infection

f

76 (14) 63 (12) 41 ( 8) 8 ( 2) 8 ( 1) < 1%

Upper respiratory tract infection

c% f

69 (13) 53 ( 10) 31 ( 6) < 1% 8 ( 1) < 1%

Pneumonia

c@

93 (17) 87 (16) 56 (10) 60 (11) 57 (11) 41 ( 8)

Respiratory tract infection

%

35 ( 7) 25 ( 5) 21 ( 4) 7 ( 1) < 1% < 1%

Influenza

f

33 ( 6) 23 ( 4) 15 ( 3) < 1% < 1% 0 ( 0)

Gastroenteritis

f

32 ( 6) 17 ( 3) 13 ( 2) 0 ( 0) < 1% < 1%

Lower respiratory tract infection 29 ( 5) 14 ( 3) 16 ( 3) 10 ( 2) < 1% < 1%

Rhinitis

f

29 ( 5) 24 ( 4) 14 ( 3) 0 ( 0) 0 ( 0) 0 ( 0)

Cellulitis

c

< 5% < 5% < 5% 8 ( 2) < 1% < 1%

Sepsis

c@

33 ( 6) 26 ( 5) 18 ( 3) 26 ( 5) 20 ( 4) 13 ( 2)

Nervous system disorders

Headache

f

75 (14) 52 ( 10) 56 (10) < 1% < 1% < 1%

Dysgeusia

f

39 ( 7) 45 ( 8) 22 ( 4) < 1% 0 ( 0.0) < 1%

Blood and lymphatic system disorders

d

Anemia 233 (44) 193 (36) 229 (42) 97 (18) 85 (16) 102 (19)

Neutropenia 186 (35) 178 (33) 328 (61) 148 (28) 143 (26) 243 (45)

Thrombocytopenia 104 (20) 100 (19) 135 (25) 44 ( 8) 43 ( 8) 60 (11)

Febrile neutropenia 7 ( 1) 17 ( 3)

15 ( 3) 6 ( 1) 16 ( 3) 14 ( 3)

Pancytopenia < 1% 6 ( 1) 7 ( 1) < 1% < 1% < 1%

Respiratory, thoracic and mediastinal disorders

Cough

f

121 (23) 94 (17) 68 (13) < 1% < 1% < 1%

Dyspnea

c,e

117 (22) 89 (16) 113 (21)

30 ( 6) 22 ( 4) 18 ( 3)

Epistaxis

f

32 ( 6) 31 ( 6) 17 ( 3) < 1% < 1% 0 ( 0)

Oropharyngeal pain

f

30 ( 6) 22 ( 4) 14 ( 3) 0 ( 0) 0 ( 0) 0 ( 0)

Dyspnea exertional

e

27 ( 5) 29 ( 5) < 5%

6 ( 1) < 1% 0 ( 0)

Metabolism and nutrition disorders

Decreased appetite 123 (23) 115 (21) 72 (13)

14 ( 3) 7 ( 1) < 1%

Hypokalemia

%

91 (17) 62 (11) 38 ( 7) 35 ( 7) 20 ( 4) 11 ( 2)

Hyperglycemia 62 (12) 52 ( 10) 19 ( 4) 28 ( 5) 23 ( 4) 9 ( 2)

Hypocalcemia 57 (11) 56 (10) 31 ( 6)

23 ( 4) 19 ( 4) 8 ( 1)

Dehydration

%

25 ( 5) 29 ( 5) 17 ( 3) 8 ( 2) 13 ( 2) 9 ( 2)

Gou

t

e

< 5% < 5% < 5% 8 ( 2) 0 ( 0) 0 ( 0)

Diabetes mellitus

% e

< 5% < 5% < 5% 8 ( 2) < 1% < 1%

Hypophosphatemia

e

< 5% < 5% < 5%

7 ( 1) < 1% < 1%

Hyponatremia

% e

< 5% < 5% < 5% 7 ( 1) 13 ( 2) 6 ( 1)

Skin and subcutaneous tissue disorders

Rash 139 (26) 151 (28) 105 (19) 39 ( 7) 38 ( 7) 33 ( 6)

Pruritus

f

47 ( 9) 49 ( 9) 24 ( 4) < 1% < 1% < 1%

Psychiatric disorders

Insomnia 147 (28) 127 (24) 53 ( 10) < 1% 6 ( 1) 0 ( 0)

Depression 58 (11) 46 ( 9) 30 ( 6) 10 ( 2) < 1% < 1%

Vascular disorders

Deep vein thrombosis

c%

55 (10) 39 ( 7) 22 ( 4)

30 ( 6) 20 ( 4) 15 ( 3)

Hypotension

c%

51 ( 10) 35 ( 6) 36 ( 7)

11 ( 2) 8 ( 1) 6 ( 1)

Injury, Poisoning, and Procedural Complications

Reference ID: 4439576

12

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

All Adverse Reactions

a

Grade 3/4 Adverse Reactions

b

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

Rd

Continuous

(N = 532)

Rd18

(N = 540)

MPT

(N = 541)

Fall

f

43 ( 8) 25 ( 5) 25 ( 5) < 1% 6 ( 1) 6 ( 1)

Contusion

f

33 ( 6) 24 ( 4) 15 ( 3) < 1% < 1% 0 ( 0)

Eye disorders

Cataract 73 (14) 31 ( 6) < 1% 31 ( 6) 14 ( 3) < 1%

Cataract subcapsula

r

e

< 5% < 5% < 5% 7 ( 1) 0 ( 0) 0 ( 0)

Investigations

Weight decreased 72 (14) 78 (14) 48 ( 9) 11 ( 2) < 1% < 1%

Cardiac disorders

Atrial fibrillation

c

37 ( 7) 25 ( 5) 25 ( 5) 13 ( 2) 9 ( 2) 6 ( 1)

Myocardial infarction (including acute)

c ,e

< 5% < 5% < 5% 10 ( 2) < 1% < 1%

Renal and Urinary disorders

Renal failure (including acute)

c@,f

49 ( 9) 54 (10) 37 ( 7) 28 ( 5) 33 ( 6) 29 ( 5)

Neoplasms benign, malignant and unspecified (Including cysts and polyps)

Squamous cell carcinoma

c e

< 5% < 5% < 5% 8 ( 2) < 1% 0 ( 0)

Basal cell carcinoma

c e,f

< 5% < 5% < 5% < 1% < 1% 0 ( 0)

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.

a

All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd

Continuous or Rd18 Arms compared to the MPT Arm.

b

All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in

either the Rd Continuous or Rd18 Arms compared to the MPT Arm.

c

Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either

the Rd Continuous or Rd18 Arms compared to the MPT Arm.

d

Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for

Rd Continuous/Rd18, and have also been reported as serious.

e

Footnote “a” not applicable.

f

Footnote “b” not applicable.

@

- adverse reactions in which at least one resulted in a fatal outcome.

%

- adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

*Adverse reactions included in combined adverse reaction terms:

Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain

Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella,

pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia

viral

Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal

sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis

Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash

with eosinophilia and systemic symptoms, erythema multiforme, rash pustular

Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

Newly Diagnosed MM - REVLIMID Maintenance Therapy Following Auto-HSCT:

Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT

until progressive disease or unacceptable toxicity. The mean treatment duration for REVLIMID treatment was 30.3 months for Maintenance Study 1 and 24.0 months

for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study

1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date

The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the

maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported

adverse reactions (more than 20% in the REVLIMID arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract

infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4

reactions (more than 20% in the REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and

neutropenia (more than 4.5%) occurred in the REVLIMID arm.

For REVLIMID, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The

most common adverse reaction leading to dose reduction of REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). The most

common adverse reactions leading to discontinuation of REVLIMID were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance

Study 2.

The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable

throughout treatment.

Table 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms.

Reference ID: 4439576

13

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 5: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the REVLIMID Vs Placebo Arms*

Body System

Adverse Reaction

Maintenance Study 1 Maintenance Study 2

All Adverse Reactions

a

Grade 3/4 Adverse

Reactions

b

All Adverse Reactions

a

Grade 3/4 Adverse

Reactions

b

REVLIMID

(N=224)

n (%)

Placebo

(N=221)

n (%)

REVLIMID

(N=224)

n (%)

Placebo

(N=221)

n (%)

REVLIMID

(N=293)

n (%)

Placebo

(N=280)

n (%)

REVLIMID

(N=293)

n (%)

Placebo

(N=280)

n (%)

Blood and lymphatic system disorders

Neutropenia

c %

177 ( 79) 94 ( 43) 133 ( 59) 73 ( 33) 178 ( 61) 33 ( 12) 158 ( 54) 21 ( 8)

Thrombocytopenia

c

%

162 ( 72) 101 ( 46) 84 ( 38) 67 ( 30) 69 ( 24) 29 ( 10) 38 ( 13) 8 ( 3)

Leukopenia

c

51 ( 23) 25 ( 11) 45 ( 20) 22 ( 10) 93 ( 32) 21 ( 8) 71 ( 24) 5 ( 2)

Anemia 47 ( 21) 27 ( 12) 23 ( 10) 18 ( 8) 26 ( 9) 15 ( 5) 11 ( 4) 3 ( 1)

Lymphopenia 40 ( 18) 29 ( 13) 37 ( 17) 26 ( 12) 13 ( 4) 3 ( 1) 11 ( 4) < 1%

Pancytopenia

c d %

< 1% 0 ( 0) 0 ( 0) 0 ( 0) 12 ( 4) < 1% 7 ( 2) < 1%

Febrile neutropenia

c

39 ( 17) 34 ( 15) 39 ( 17) 34 ( 15) 7 ( 2) < 1% 5 ( 2) < 1%

Infections and infestations

#

Upper respiratory

tract infection

e

60 ( 27) 35 ( 16) 7 ( 3) 9 ( 4) 32 ( 11) 18 ( 6) < 1% 0 ( 0)

Neutropenic infection 40 ( 18) 19 ( 9) 27 ( 12) 14 ( 6) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0)

Pneumonias*

c %

31 ( 14) 15 ( 7) 23 ( 10) 7 ( 3) 50 ( 17) 13 ( 5) 27 ( 9) 5 ( 2)

Bronchitis

c

10 ( 4) 9 ( 4) < 1% 5 ( 2) 139 ( 47) 104 ( 37) 4 ( 1) < 1%

Nasopharyngitis

e

5 ( 2) < 1% 0 ( 0) 0 ( 0) 102 ( 35) 84 ( 30) < 1% 0 ( 0)

Gastroenteritis

c

0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 66 ( 23) 55 ( 20) 6 ( 2) 0 ( 0)

Rhinitis

e

< 1% 0 ( 0) 0 ( 0) 0 ( 0) 44 ( 15) 19 ( 7) 0 ( 0) 0 ( 0)

Sinusitis

e

8 ( 4) 3 ( 1) 0 ( 0) 0 ( 0) 41 ( 14) 26 ( 9) 0 ( 0) < 1%

Influenza

c

8 ( 4) 5 ( 2) < 1% < 1% 39 ( 13) 19 ( 7) 3 ( 1) 0 ( 0)

Lung infection

c

21 ( 9) < 1% 19 ( 8) < 1% 9 ( 3) 4 ( 1) < 1% 0 ( 0)

Lower respiratory

tract infection

e

13 ( 6) 5 ( 2) 6 ( 3) 4 ( 2) 4 ( 1) 4 ( 1) 0 ( 0) < 1%

Infection

c

12 ( 5) 6 ( 3) 9 ( 4) 5 ( 2) 17 ( 6) 5 ( 2) 0 ( 0) 0 ( 0)

Urinary tract

infection

c d e

9 ( 4) 5 ( 2) 4 ( 2) 4 ( 2)

22 ( 8) 17 ( 6) < 1% 0 ( 0)

Lower respiratory

tract infection

bacterial

d

6 ( 3) < 1% 4 ( 2) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0)

Bacteremia

d

5 ( 2) 0 ( 0) 4 ( 2) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0)

Herpes zoster

c d

11 ( 5) 10 ( 5) 3 ( 1) < 1% 29 ( 10) 25 ( 9) 6 ( 2) < 1%

Sepsis*

c d @

< 1% < 1% 0 ( 0) 0 ( 0) 6 ( 2) < 1% 4 ( 1) < 1%

Gastrointestinal disorders

Diarrhea 122 ( 54) 83 ( 38) 22 ( 10) 17 ( 8) 114 ( 39) 34 ( 12) 7 ( 2) 0 ( 0)

Nausea

e

33 ( 15) 22 ( 10) 16 ( 7) 10 ( 5) 31 ( 11) 28 ( 10) 0 ( 0) 0 ( 0)

Vomiting 17 ( 8) 12 ( 5) 8 ( 4) 5 ( 2) 16 ( 5) 15 ( 5) < 1% 0 ( 0)

Constipation

e

12 ( 5) 8 ( 4) 0 ( 0) 0 ( 0) 37 ( 13) 25 ( 9) < 1% 0 ( 0)

Abdominal pain

e

8 ( 4) 7 ( 3) < 1% 4 ( 2) 31 ( 11) 15 ( 5) < 1% < 1%

Abdominal pain

upper

e

0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 20 ( 7) 12 ( 4) < 1% 0 ( 0)

General disorders and administration site conditions

Asthenia 0 ( 0) < 1% 0 ( 0) 0 ( 0) 87 ( 30) 53 ( 19) 10 ( 3) < 1%

Fatigue 51 ( 23) 30 ( 14) 21 ( 9) 9 ( 4) 31 ( 11) 15 ( 5) 3 ( 1) 0 ( 0)

Pyrexia

e

17 ( 8) 10 ( 5) < 1% < 1% 60 ( 20) 26 ( 9) < 1% 0 ( 0)

Reference ID: 4439576

14

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

Maintenance Study 1 Maintenance Study 2

All Adverse Reactions

a

Grade 3/4 Adverse

Reactions

b

All Adverse Reactions

a

Grade 3/4 Adverse

Reactions

b

REVLIMID

(N=224)

n (%)

Placebo

(N=221)

n (%)

REVLIMID

(N=224)

n (%)

Placebo

(N=221)

n (%)

REVLIMID

(N=293)

n (%)

Placebo

(N=280)

n (%)

REVLIMID

(N=293)

n (%)

Placebo

(N=280)

n (%)

Skin and subcutaneous tissue disorders

Dry skin

e

9 ( 4) 4 ( 2) 0 ( 0) 0 ( 0) 31 ( 11) 21 ( 8) 0 ( 0) 0 ( 0)

Rash 71 ( 32) 48 ( 22) 11 ( 5) 5 ( 2) 22 ( 8) 17 ( 6) 3 ( 1) 0 ( 0)

Pruritus 9 ( 4) 4 ( 2) 3 ( 1) 0 ( 0) 21 ( 7) 25 ( 9) < 1% 0 ( 0)

Nervous system disorders

Paresthesia

e

< 1% 0 ( 0) 0 ( 0) 0 ( 0) 39 ( 13) 30 ( 11) < 1% 0 ( 0)

Peripheral

neuropathy*

e

34 ( 15) 30 ( 14) 8 ( 4) 8 ( 4) 29 ( 10) 15 ( 5) 4 ( 1) < 1%

Headache

d

11 ( 5) 8 ( 4) 5 ( 2) < 1% 25 ( 9) 21 ( 8) 0 ( 0) 0 ( 0)

Investigations

Alanine

aminotransferase

increased

16 ( 7) 3 ( 1) 8 ( 4) 0 ( 0) 5 ( 2) 5 ( 2) 0 ( 0) < 1%

Aspartate

aminotransferase

increased

d

13 ( 6) 5 ( 2) 6 ( 3) 0 ( 0) < 1% 5 ( 2) 0 ( 0) 0 ( 0)

Metabolism and nutrition disorders

Hypokalemia 24 ( 11) 13 ( 6) 16 ( 7) 12 ( 5) 12 ( 4) < 1% < 1% 0 ( 0)

Dehydration 9 ( 4 ) 5 ( 2) 7 ( 3) 3 ( 1) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0)

Hypophosphatemia

d

16 ( 7) 15 ( 7) 13 ( 6) 14 ( 6) 0 ( 0) < 1% 0 ( 0) 0 ( 0)

Musculoskeletal and connective tissue disorders

Muscle spasms

e

0 ( 0) < 1% 0 ( 0) 0 ( 0) 98 ( 33) 43 ( 15) < 1% 0 ( 0)

Myalgia

e

7 ( 3) 8 ( 4) 3 ( 1) 5 ( 2) 19 ( 6) 12 ( 4) < 1% < 1%

Musculoskeletal pain

e

< 1% < 1% 0 ( 0) 0 ( 0) 19 ( 6) 11 ( 44) 0 ( 0) 0 ( 0)

Hepatobiliary disorders

Hyperbilirubinemia

e

34 ( 15) 19 ( 9) 4 ( 2) < 1% 4 ( 1) < 1% < 1% 0 ( 0)

Respiratory, thoracic and mediastinal disorders

Cough

e

23 ( 10) 12 ( 5) 3 ( 1) < 1% 80 ( 27) 56 ( 20) 0 ( 0) 0 ( 0)

Dyspnea

c e

15 ( 7) 9 ( 4) 8 ( 4) 4 ( 2) 17 ( 6) 9 ( 3) < 1% 0 ( 0)

Rhinorrhea

e

0 ( 0) 3 ( 1) 0 ( 0) 0 ( 0) 15 ( 5) 6 ( 2) 0 ( 0) 0 ( 0)

Pulmonary embolism

c d e

0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 3 ( 1) 0 ( 0) < 1% 0 ( 0)

Vascular disorders

Deep vein

thrombosis*

c d %

8 ( 4) < 1% 5 ( 2) < 1% 7 ( 2) < 1% 4 ( 1) < 1%

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Myelodysplastic

syndrome

c d e

5 ( 2) 0 ( 0) < 1% 0 ( 0) 3 ( 1) 0 ( 0) < 1% 0 ( 0)

Note: Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is

counted only once under the applicable Body System/Adverse Reaction.

a

All treatment-emergent AEs in at least 5% of patients in the REVLIMID Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance

group.

b

All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo

Maintenance group.

c

All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo

Maintenance group.

d

Footnote “a” not applicable for either study

e

Footnote “b” not applicable for either study

@

-ADRs where at least one resulted in a fatal outcome

%

- ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases)

# - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed

*Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]):

Reference ID: 4439576

15

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Pneumonias Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia

mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis

Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis

Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy

Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis

After At Least One Prior Therapy for MM:

Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350

patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to

199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the

REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the

placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of

REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Table 6: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the

REVLIMID/dexamethasone and Placebo/dexamethasone Groups

Body System

Adverse Reaction

REVLIMID/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Neutropenia

%

149 (42) 22 ( 6)

Anemia

@

111 (31) 83 (24)

Thrombocytopenia

@

76 (22) 37 (11)

Leukopenia 28 ( 8) 4 ( 1)

Lymphopenia 19 ( 5) 5 ( 1)

General disorders and administration site conditions

Fatigue 155 (44) 146 (42)

Pyrexia 97 (27) 82 (23)

Peripheral edema 93 (26) 74 (21)

Chest pain 29 ( 8) 20 ( 6)

Lethargy 24 ( 7) 8 ( 2)

Gastrointestinal disorders

Constipation 143 (41) 74 (21)

Diarrhea

@

136 (39) 96 (27)

Nausea

@

92 (26) 75 (21)

Vomiting

@

43 (12) 33 ( 9)

Abdominal pain

@

35 ( 10) 22 ( 6)

Dry mouth 25 ( 7) 13 ( 4)

Musculoskeletal and connective tissue disorders

Muscle cramp 118 (33) 74 (21)

Back pain 91 (26) 65 (19)

Bone pain 48 (14) 39 (11)

Pain in limb 42 (12) 32 ( 9)

Nervous system disorders

Dizziness 82 (23) 59 (17)

Tremor 75 (21) 26 ( 7)

Dysgeusia 54 (15) 34 ( 10)

Hypoesthesia 36 (10) 25 ( 7)

Neuropathyª 23 ( 7) 13 ( 4)

Respiratory, thoracic and mediastinal disorders

Dyspnea 83 (24) 60 (17)

Nasopharyngitis 62 (18) 31 ( 9)

Pharyngitis 48 (14) 33 ( 9)

Bronchitis 40 (11) 30 ( 9)

Infections

b

and infestations

Reference ID: 4439576

16

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

REVLIMID/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Upper respiratory tract infection 87 (25) 55 (16)

Pneumonia

@

48 (14) 29 ( 8)

Urinary tract infection 30 ( 8) 19 ( 5)

Sinusitis 26 ( 7) 16 ( 5)

Skin and subcutaneous system disorders

Rash

c

75 (21) 33 ( 9)

Sweating increased 35 ( 10) 25 ( 7)

Dry skin 33 ( 9) 14 ( 4)

Pruritus 27 ( 8) 18 ( 5)

Metabolism and nutrition disorders

Anorexia 55 (16) 34 ( 10)

Hypokalemia 48 (14) 21 ( 6)

Hypocalcemia 31 ( 9) 10 ( 3)

Appetite decreased 24 ( 7) 14 ( 4)

Dehydration 23 ( 7) 15 ( 4)

Hypomagnesemia 24 ( 7) 10 ( 3)

Investigations

Weight decreased 69 (20) 52 (15)

Eye disorders

Blurred vision 61 (17) 40 (11)

Vascular disorders

Deep vein thrombosis

%

33 ( 9) 15 ( 4)

Hypertension 28 ( 8) 20 ( 6)

Hypotension 25 ( 7) 15 ( 4)

Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the

REVLIMID/dexamethasone and Placebo/dexamethasone groups

Body System

Adverse Reaction

REVLIMID/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Neutropenia

%

118 (33) 12 ( 3)

Thrombocytopenia

@

43 (12) 22 ( 6)

Anemia

@

35 ( 10) 20 ( 6)

Leukopenia 14 ( 4) < 1%

Lymphopenia 10 ( 3) 4 ( 1)

Febrile neutropenia

%

8 ( 2) 0 ( 0)

General disorders and administration site conditions

Fatigue 23 ( 7) 17 ( 5)

Vascular disorders

Deep vein thrombosis

%

29 ( 8) 12 ( 3)

Infections and infestations

Pneumonia

@

30 ( 8) 19 ( 5)

Urinary tract infection 5 ( 1) < 1%

Metabolism and nutrition disorders

Hypokalemia 17 ( 5) 5 ( 1)

Hypocalcemia 13 ( 4) 6 ( 2)

Hypophosphatemia 9 ( 3) 0 ( 0)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism

@

14 ( 4) < 1%

Respiratory distress

@

4 ( 1) 0 ( 0)

Reference ID: 4439576

17

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

REVLIMID/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Musculoskeletal and connective tissue disorders

Muscle weakness 20 ( 6) 10 ( 3)

Gastrointestinal disorders

Diarrhea

@

11 ( 3) 4 ( 1)

Constipation 7 ( 2) < 1%

Nausea

@

6 ( 2) < 1%

Cardiac disorders

Atrial fibrillation

@

13 ( 4) 4 ( 1)

Tachycardia 6 ( 2) < 1%

Cardiac failure congestive

@

5 ( 1) < 1%

Nervous system disorders

Syncope 10 ( 3) < 1%

Dizziness 7 ( 2) < 1%

Eye disorders

Cataract 6 ( 2) < 1%

Cataract unilateral 5 ( 1) 0 ( 0)

Psychiatric disorder

Depression 10 ( 3) 6 ( 2)

Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the

REVLIMID/dexamethasone and Placebo/dexamethasone Groups

Body System

Adverse Reaction

REVLIMID/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Febrile neutropenia

%

6 ( 2) 0 ( 0)

Vascular disorders

Deep vein thrombosis

%

26 ( 7) 11 ( 3)

Infections and infestations

Pneumonia

@

33 ( 9) 21 ( 6)

Respiratory, thoracic, and mediastinal disorders

Pulmonary embolism

@

13 ( 4) < 1%

Cardiac disorders

Atrial fibrillation

@

11 ( 3) < 1%

Cardiac failure congestive

@

5 ( 1) 0 ( 0)

Nervous system disorders

Cerebrovascular accident

@

7 ( 2) < 1%

Gastrointestinal disorders

Diarrhea

@

6 ( 2) < 1%

Musculoskeletal and connective tissue disorders

Bone pain 4 ( 1) 0 ( 0)

For Tables 6, 7 and 8 above:

@

- adverse reactions in which at least one resulted in a fatal outcome.

%

- adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with

placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups

REVLIMID/dexamethasone vs. placebo/dexamethasone.

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]

VTE and ATE are increased in patients treated with REVLIMID.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group

compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to

DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%),

Reference ID: 4439576

18

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%).

Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group

compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE

adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous,

Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade

3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6

% and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone

group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades:

2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and

MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9%

respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the

placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%,

0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were

reported:

Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia

Cardiac disorders: bradycardia, myocardial infarction, angina pectoris

Endocrine disorders: hirsutism

Eye disorders: blindness, ocular hypertension

Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia

General disorders and administration site conditions: malaise

Investigations: liver function tests abnormal, alanine aminotransferase increased

Nervous system disorders: cerebral ischemia

Psychiatric disorders: mood swings, hallucination, loss of libido

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: cough, hoarseness

Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation

Myelodysplastic Syndromes:

A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148

patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse reactions were related to blood and lymphatic system

disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions

observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that

were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4

adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions

that are drug-related and those that reflect the patient’s underlying disease.

Table 9: Summary of Adverse Reactions Reported in ≥5% of the

REVLIMID Treated Patients in del 5q MDS Clinical Study

Body System

Adverse Reaction

a

10 mg Overall

(N=148)

Patients with at least one adverse reaction 148 (100)

Blood and Lymphatic System Disorders

Thrombocytopenia

Neutropenia

Anemia

Leukopenia

Febrile Neutropenia

91 (61)

87 (59)

17 (11)

12 (8)

8 (5)

Skin and Subcutaneous Tissue Disorders

Pruritus

Rash

Dry Skin

Contusion

Night Sweats

Sweating Increased

Ecchymosis

62 (42)

53 (36)

21 (14)

12 (8)

10 (7)

8 (5)

Reference ID: 4439576

19

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

a

10 mg Overall

(N=148)

Erythema 8 (5)

Gastrointestinal Disorders

Diarrhea

Constipation

Nausea

Abdominal Pain

Vomiting

Abdominal Pain Upper

Dry Mouth

Loose Stools

72 (49)

35 (24)

18 (12)

15 (10)

12 (8)

10 (7)

9 (6)

Respiratory, Thoracic and Mediastinal Disorders

Nasopharyngitis

Cough

Dyspnea

Pharyngitis

Epistaxis

Dyspnea Exertional

Rhinitis

Bronchitis

34 (23)

29 (20)

25 (17)

23 (16)

22 (15)

10 (7)

9 (6)

General Disorders and Administration Site Conditions

Fatigue

Pyrexia

Edema Peripheral

Asthenia

Edema

Pain

Rigors

Chest Pain

46 (31)

31 (21)

30 (20)

22 (15)

15 (10)

10 (7)

9 (6)

8 (5)

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Back Pain

Muscle Cramp

Pain in Limb

Myalgia

Peripheral Swelling

32 (22)

31 (21)

27 (18)

16 (11)

13 (9)

12 (8)

Nervous System Disorders

Dizziness

Headache

Hypoesthesia

Dysgeusia

Peripheral Neuropathy

29 (20)

10 (7)

9 (6)

8 (5)

Infections and Infestations

Upper Respiratory Tract Infection

Pneumonia

Urinary Tract Infection

Sinusitis

Cellulitis

22 (15)

17 (11)

16 (11)

12 (8)

8 (5)

Metabolism and Nutrition Disorders

Hypokalemia

Anorexia

Hypomagnesemia

16 (11)

15 (10)

9 (6)

Investigations

Alanine Aminotransferase Increased 12 (8)

Psychiatric Disorders

Insomnia

Depression

15 (10)

8 (5)

Renal and Urinary Disorders

Dysuria 10 (7)

Vascular Disorders

Hypertension 9 ( 6)

Endocrine Disorders

Acquired Hypothyroidism 10 (7)

Cardiac Disorders

Palpitations 8 (5)

Reference ID: 4439576

20

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

a

Body System and adverse reactions are coded using the MedDRA dictionary. Body System

and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple

occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions

1

Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

Adverse Reactions

2

10 mg

(N=148)

Patients with at least one Grade 3/4 AE 131 (89)

Neutropenia 79 (53)

Thrombocytopenia 74 (50)

Pneumonia 11 (7)

Rash 10 (7)

Anemia 9 (6)

Leukopenia 8 (5)

Fatigue 7 (5)

Dyspnea 7 (5)

Back Pain 7 (5)

Febrile Neutropenia 6 (4)

Nausea 6 (4)

Diarrhea 5 (3)

Pyrexia 5 (3)

Sepsis 4 (3)

Dizziness 4 (3)

Granulocytopenia 3 (2)

Chest Pain 3 (2)

Pulmonary Embolism 3 (2)

Respiratory Distress 3 (2)

Pruritus 3 (2)

Pancytopenia 3 (2)

Muscle Cramp 3 (2)

Respirato

r

y Tract Infection 2 (1)

Upper Respiratory Tract Infection 2 (1)

Asthenia 2 (1)

Multi-organ Failure 2 (1)

Epistaxis 2 (1)

Hypoxia 2 (1)

Pleural Effusion 2 (1)

Pneumonitis 2 (1)

Pulmonary Hypertension 2 (1)

Vomiting 2 (1)

Sweating Increased 2 (1)

Arthralgia 2 (1)

Pain in Limb 2 (1)

Headache 2 (1)

Syncope 2 (1)

1

Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common

Toxicity Criteria version 2.

2

Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only

once in the adverse reaction category.

In other clinical studies of REVLIMID in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in

Table 9 or 10 were reported:

Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia,

refractory anemia

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial

infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia,

ventricular dysfunction

Ear and labyrinth disorders: vertigo

Endocrine disorders: Basedow’s disease

Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis,

gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis,

perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure

Reference ID: 4439576

21

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Immune system disorders: hypersensitivity

Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection

NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis,

Staphylococcal infection, urosepsis

Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture,

overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased

Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia

Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate

cancer metastatic

Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal

cord compression, subarachnoid hemorrhage, transient ischemic attack

Psychiatric disorders: confusional state

Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass

Reproductive system and breast disorders: pelvic pain

Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial

lung disease, lung infiltration, wheezing

Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis

Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis

Mantle Cell Lymphoma:

In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134

(81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this

study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or

more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51

patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions.

Table 11: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients)

in Mantle Cell Lymphoma

Body System

Adverse Reaction

All Adverse Reactions

1

(N=134)

n (%)

Grade 3/4 Adverse

Reactions

2

(N=134)

n (%)

General disorders and administration site conditions

Fatigue 45 (34) 9 (7)

Pyrexia

$

31 (23) 3 (2)

Edema peripheral 21 (16) 0

Asthenia

$

19 (14) 4 (3)

General physical health deterioration 3 (2) 2 (1)

Gastrointestinal disorders

Diarrhea

$

42 (31) 8 (6)

Nausea

$

40 (30) 1 (<1)

Constipation 21 (16) 1 (<1)

Vomiting

$

16 (12) 1 (<1)

Abdominal pain

$

13 (10) 5 ( 4)

Musculoskeletal and connective tissue disorders

Back pain 18 (13) 2 (1)

Muscle spasms 17 (13) 1 (<1)

Arthralgia 11 (8) 2 (1)

Muscular weakness

$

8 (6) 2 ( 1)

Respiratory, thoracic and mediastinal disorders

Cough 38 (28) 1 (<1)

Reference ID: 4439576

22

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction

All Adverse Reactions

1

(N=134)

n (%)

Grade 3/4 Adverse

Reactions

2

(N=134)

n (%)

Dyspnea

$

24 (18) 8 (6)

Pleural Effusion 10 (7) 2 (1)

Hypoxia 3 (2) 2 (1)

Pulmonary embolism 3 (2) 2 ( 1)

Respiratory distress

$

2 (1) 2 (1)

Oropharyngeal pain 13 (10) 0

Infections and infestations

Pneumonia

@ $

19 (14) 12 (9)

Upper respiratory tract infection 17 (13) 0

Cellulitis

$

3 (2) 2 (1)

Bacteremia

$

2 (1) 2 (1)

Staphylococcal sepsis

$

2 (1) 2 (1)

Urinary tract infection

$

5 (4) 2 (1)

Skin and subcutaneous tissue disorders

Rash

+

30 (22) 2 (1)

Pruritus 23 (17) 1 (<1)

Blood and lymphatic system disorders

Neutropenia 65 (49) 58 (43)

Thrombocytopenia

% $

48 (36) 37 (28)

Anemia

$

41 (31) 15 (11)

Leukopenia

$

20 (15) 9 (7)

Lymphopenia 10 ( 7) 5 (4)

Febrile neutropenia

$

8 (6) 8 (6)

Metabolism and nutrition disorders

Decreased appetite 19 (14) 1 (<1)

Hypokalemia 17 (13) 3 (2)

Dehydration

$

10 (7) 4 (3)

Hypocalcemia 4 (3) 2 (1)

Hyponatremia 3 (2) 3 (2)

Renal and urinary disorders

Renal failure

$

5 (4) 2 (1)

Vascular disorders

Hypotension

@ $

9 (7) 4 (3)

Deep vein thrombosis

$

5 (4) 5 (4)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumor flare 13 (10) 0

Squamous cell carcinoma of skin

$

4 (3) 4 (3)

Investigations

Weight decreased 17 (13) 0

1

-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects.

2

-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects.

$

-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects.

@

- Adverse reactions where at least one resulted in a fatal outcome.

%

- Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases).

#

- All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed.

+

- All adverse reactions under HLT of Rash will be considered listed.

Reference ID: 4439576

23

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in

patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Cardiac disorder: Cardiac failure

Ear and labyrinth disorders: Vertigo

General disorders and administration site conditions: Chills

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes

Musculoskeletal and connective tissue disorders: Pain in extremity

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy

Psychiatric disorders: Insomnia

Skin and subcutaneous tissue disorders: Dry skin, night sweats

The following serious adverse reactions not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Blood and lymphatic system disorders: Neutropenia

Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia

Infections and infestations: Clostridium difficile colitis, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma

Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism

Follicular Lymphoma or Marginal Zone Lymphoma

The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials;

AUGMENT (N=176) and MAGNIFY (N=222) [see Clinical Studies (14.4)]. Subjects were 18 years or older in age, had an ECOG PS ≤2, ANC ≥1,000 cells/mm

3

and

platelets≥ 75,000/mm

3

(unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥8g/dL, AST and ALT ≤ 3x ULN (unless documented liver

involvement with lymphoma, and creatinine clearance of ≥ 30mL/min. Subjects with active HIV, hepatitis B or C were not eligible.

In the AUGMENT trial, patients received REVLIMID 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m

2

weekly (days 1, 8, 15 and

22 in cycle 1) then on day 1 of cycles 2-5 (n=176) or placebo with rituximab 375 mg/m

2

weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=180) for

up to 12 cycles. In the MAGNIFY trial, patients received REVLIMID 20 mg by mouth daily, days 1-21 of each 28 day cycle with rituximab 375 mg/m

2

weekly (days 1,

8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 7, 9 and 11 in the induction phase of the trial (n=222). In the AUGMENT trial, 88.1% of patients completed at least 6

cycles of REVLIMID/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6

cycles of REVLIMID/rituximab, and 30.6% of patients completed 12 cycles.

Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White.

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia,

cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving

REVLIMID/rituximab on AUGMENT and 29% on MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the

REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of

patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was

neutropenia (4.8%).

The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%),

and cough (20%).

Table 12: All Grade Adverse Reactions ( ≥5%) or Grade 3/4 Adverse Reactions ( ≥1%) in Patients with FL and

MZL with a Difference Between Arms of >1% When Compared to Control Arm in AUGMENT Trial

Body System

Adverse Reaction*

All Adverse Reactions

1

Grade 3 / 4 Adverse Reactions

2

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

Infections and infestations

Upper respiratory tract

infection

32 (18) 23 (13) 2 (1.1) 4 (2.2)

Influenza

%

17 (10) 8 (4.4) 1 (< 1) 0 (0)

Pneumonia

3,$,%

13 (7) 6 (3.3) 6 (3.4) 4 (2.2)

Sinusitis 13 (7) 5 (2.8) 0 (0) 0 (0)

Urinary tract infection

$

13 (7) 7 (3.9) 1 (< 1) 1 (< 1)

Bronchitis 8 (4.5) 6 (3.3) 2 (1.1) 0 (0)

Gastroenteritis

$

6 (3.4) 4 (2.2) 2 (1.1) 0 (0)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumor flare

$

19 (11) 1 (< 1) 1 (< 1) 0 (0)

Blood and lymphatic disorders

Neutropenia

3,$, %

102 (58) 40 (22) 88 (50) 23 (13)

Reference ID: 4439576

24

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction*

All Adverse Reactions

1

Grade 3 / 4 Adverse Reactions

2

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

Leukopenia

$,%

36 (20) 17 (9) 12 (7) 3 (1.7)

Anemia

3,$

28 (16) 8 (4.4) 8 (4.5) 1 (< 1)

Thrombocytopenia

3,$,%

26 (15) 8 (4.4) 4 (2.3) 2 (1.1)

Lymphopenia 8 (4.5) 14 (8) 5 (2.8) 2 (1.1)

Febrile

Neutropenia

3,$,%

5 (2.8) 1 (< 1) 5 (2.8) 1 (< 1)

Metabolism and nutrition disorders

Decreased Appetite 23 (13) 11 (6) 2 (1.1) 0 (0)

Hypokalemia

%

14 (8) 5 (2.8) 4 (2.3) 0 (0)

Hyperuricemia 10 (6) 8 (4.4) 1 (< 1) 1 (< 1)

Nervous system disorders

Headache 26 (15) 17 (9) 1 (< 1) 0 (0)

Dizziness 15 (9) 9 (5) 0 (0) 0 (0)

Vascular disorders

Hypotension

%

9 (5) 1 (< 1) 1 (< 1) 0 (0)

Thromboembolic

events

a,$

8 (4.5) 2 (1.1) 4 (2.3) 2 (1.1)

Respiratory, thoracic and mediastinal disorders

Cough

b

43 (24) 35 (19) 1 (< 1) 0 (0)

Dyspnea

$

19 (11) 8 (4.4) 2 (1.1) 1 (< 1)

Oropharyngeal pain 10 (6) 8 (4.4) 0 (0) 0 (0)

Pulmonary

Embolism

3,$

4 (2.3) 1 (< 1) 4 (2.3) 1 (< 1)

Chronic obstructive

pulmonary disease

$

3 (1.7) 0 (0) 2 (1.1) 0 (0)

Respiratory failure

3,$

2 (1.1) 1 (< 1) 2 (1.1) 0 (0)

Gastrointestinal disorders

Diarrhea

$,%

55 (31) 41 (23) 5 (2.8) 0 (0)

Constipation 46 (26) 25 (14) 0 (0) 0 (0)

Abdominal pain

c ,$

32 (18) 20 (11) 2 (1.1) 0 (0)

Vomiting

$

17 (10) 13 (7) 0 (0) 0 (0)

Dyspepsia 16 (9) 5 (2.8) 0 (0) 0 (0)

Stomatitis 9 (5) 7 (3.9) 0 (0) 0 (0)

Skin and subcutaneous tissue disorders

Rash

$,d

39 (22) 14 (8) 5 (2.8) 2 (1.1)

Pruritus

$,e

36 (20) 9 (5) 2 (1.1) 0 (0)

Dry skin 9 (5) 6 (3.3) 0 (0) 0 (0)

Dermatitis acneiform 8 (4.5) 0 (0) 2 (1.1) 0 (0)

Musculoskeletal and connective tissue disorders

Muscle Spasms 23 (13) 9 (5) 1 (< 1) 1 (< 1)

Pain in Extremity

$

8 (4.5) 9 (5) 2 (1) 0 (0)

Renal disorders

Acute Kidney

Injury

3,$,@,%

3 (1.7) 0 (0) 2 (1.1) 0 (0)

Reference ID: 4439576

25

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Body System

Adverse Reaction*

All Adverse Reactions

1

Grade 3 / 4 Adverse Reactions

2

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

REVLIMID +

Rituximab Arm

(N=176)

n (%)

Rituximab + Placebo

(Control Arm)

(N=180)

n (%)

Cardiac disorders

Supraventricular

tachycardia

3,$

2 (1.1) 0 (0) 2 (1.1) 0 (0)

General disorders and administration site conditions

Fatigue 38 (22) 33 (18) 2 (1.1) 1 (< 1)

Pyrexia

3,$

37 (21) 27 (15) 1 (< 1) 3 (1.7)

Asthenia

$,%

24 (14) 19 (11) 2 (1.1) 1 (< 1)

Edema Peripheral

$

23 (13) 16 (9) 0 (0) 0 (0)

Chills 14 (8) 8 (4.4) 0 (0) 0 (0)

Malaise 13 (7) 10 (6) 0 (0) 0 (0)

Influenza like illness 9 (5) 7 (3.9) 0 (0) 0 (0)

Psychiatric disorders

Insomnia 14 (8) 11 (6) 0 (0) 0 (0)

Investigations

Alanine

Aminotransferase

Increased

18 (10) 15 (8) 3 (1.7) 1 (< 1)

WBC count decreased 16 (9) 13 (7) 5 (2.8) 2 (1.1)

Lymphocyte count

decreased

12 (7) 12 (7) 6 (3.4) 2 (1.1)

Blood bilirubin

increased

10 (6) 0 (0) 0 (0) 0 (0)

Weight Decreased 12 (7) 2 (1.1) 0 (0) 0 (0)

Note: Adverse reactions are coded to body system/adverse reaction using MedDRA 21. A patient with multiple occurrences of an adverse

reaction is counted only once under the applicable Body System/Adverse reaction.

1

All treatment-emergent AEs in at least 5% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the

rituximab + placebo group (control arm).

2

All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%)

than the rituximab + placebo group (control arm).

3

All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than

the rituximab + placebo group (control arm).

$

Serious ADR reported.

@

- adverse reactions in which at least one resulted in a fatal outcome.

%

- adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death

cases).

*Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]):

a “Thromboembolic events” combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident,

embolism, and thrombosis.

b “Cough” combined AE term includes the following PTs: cough and productive cough.

c “Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper.

d “Rash” combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and

rash generalized.

e “Pruritus” combined AE term includes the following PTs: pruritius, pruritus generalized, rash pruritic, and pruritus allergic.

Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. Because these reactions are reported

voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see

Warnings and Precautions Section (5.8 to 5.11, and 5.13)]

Endocrine disorders: Hypothyroidism, hyperthyroidism

Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient

abnormal liver laboratory tests

Immune system disorders: Angioedema, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection

Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)

Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

Reference ID: 4439576

26

6.2

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

7 DRUG INTERACTIONS

7.1 Digoxin

When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin C

max

and AUC

inf

were increased by 14%. Periodically monitor digoxin

plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of REVLIMID.

7.2 Concomitant Therapies That May Increase the Risk of Thrombosis

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a

benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

7.3 Warfarin

Co-administration of multiple doses of REVLIMID (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and

S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by

concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is

recommended in patients with MM taking concomitant warfarin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male

patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID

to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Risk Summary

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies [see Data], REVLIMID can cause embryo-fetal harm when

administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4.1), and Use in Specific Populations (5.1)].

REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia

(absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent

external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital

malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Lenalidomide caused thalidomide-type limb defects in monkey offspring. Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats

[see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a

fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in

reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-

1088 and also to Celgene Corporation at 1-888-423-5436.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect,

loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of

clinically recognized pregnancies.

Data

Animal data

In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys

received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended

human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and

no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on

the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The

male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring.

As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were

approximately 20-40% of the maternal C

max.

Following a single oral dose to pregnant rats, lenalidomide was detected in fetal plasma and tissues; concentrations of

radioactivity in fetal tissues were generally lower than those in maternal tissues. These data indicated that lenalidomide crossed the placenta.

8.2 Lactation

Risk Summary

There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed child, or the effects of REVLIMID on milk

production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children from REVLIMID, advise women

not to breastfeed during treatment with REVLIMID.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Reference ID: 4439576

27

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive

potential prior to initiating REVLIMID therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy,

while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.

Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the

second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive

potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If

menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period

or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

Contraception

Females

Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control

simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants),

or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4

weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of REVLIMID

therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be

referred to a qualified provider of contraceptive methods, if needed.

Males

Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with

females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

Male patients taking REVLIMID must not donate sperm.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

MM In Combination: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35%

(561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall,

across all treatment arms, the frequency in most of the adverse reaction categories (eg, all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was

higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 adverse reactions in the General Disorders and Administration Site

Conditions body system were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment

arms. Grade 3 or 4 adverse reactions in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and

Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently

(<5% difference), in older subjects than in younger subjects across all treatment arms. For other body systems (e.g., Blood and Lymphatic System Disorders, Infections

and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger

subjects across all treatment arms Serious adverse reactions were generally reported at a higher frequency in the older subjects than in the younger subjects across all

treatment arms.

MM Maintenance Therapy: Overall, 10% (106/1018) of patients were 65 years of age or older, while no patients were over 75 years of age. Grade 3 or 4 adverse

reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients. The frequency of Grade 3 or 4

adverse reactions in the Blood and Lymphatic System Disorders were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older

versus younger patients. There were not a sufficient number of patients 65 years of age or older in REVLIMID maintenance studies who experienced either a serious

adverse reaction, or discontinued therapy due to an adverse reaction to determine whether elderly patients respond relative to safety differently from younger patients.

MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were

age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups.

Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤

65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed

between patients over 65 years of age and younger patients.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of

adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65

years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse

reactions than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse

reactions was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse reactions was also similar

in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients

(55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

FL or MZL in Combination: Overall, 48% (282/590) of patients were 65 years of age or older, while 14% (82/590) of patients were over 75 years of age. The overall

frequency of adverse reactions was similar in patients 65 years of age or older and younger patients for both studies pooled (98%). Grade 3 or 4 adverse reactions were

higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients (71% versus 59%). The frequency of Grade 3 or 4

adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in the Blood and Lymphatic

System Disorders (47% versus 40%) and Infections and Infestations (16% versus 11%). Serious adverse reactions were higher in the REVLIMID arm (more than 5%

higher) in the patients 65 years of age or older versus younger patients (37% versus 18%). The frequency of serious adverse reactions were higher in the REVLIMID

arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in Infections and Infestations (15% versus 6%).

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

8.6 Renal Impairment

Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis [see Dosage and Administration (2.5)].

Reference ID: 4439576

28

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

12

10 OVERDOSAGE

There is no specific experience in the management of REVLIMID overdose in patients with MM, MDS, MCL, FL, or MZL. In dose-ranging studies in healthy subjects,

some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and

elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

11 DESCRIPTION

REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-

dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:

N

H

O

NH

2

3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

The empirical formula for lenalidomide is C

13

H

13

N

3

O

3,

and the gram molecular weight is 259.3.

Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble

in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an

asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.

REVLIMID is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient

and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule

shell contains gelatin, titanium dioxide and black ink. The 2.5 mg and 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and

black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink. The 20 mg capsule shell contains gelatin, FD&C blue #2, yellow

iron oxide, titanium dioxide and black ink.

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated

through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos,

Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits

proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular

lymphoma and marginal zone lymphoma in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM.

Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-

dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-

inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell

proliferation and the induction of apoptosis. The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells

and increases ADCC in marginal zone lymphoma cells compared to rituximab alone in vitro.

Reference ID: 4439576

29

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a thorough QT study. At a dose two times the maximum recommended

dose, lenalidomide did not prolong the QTc interval. The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was

below 10 ms.

12.3 Pharmacokinetics

Absorption

Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of REVLIMID in patients with MM or MDS, the maximum

plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and

C

max

values increasing proportionally with dose. Multiple doses of REVLIMID at the recommended dosage does not result in drug accumulation.

Administration of a single 25 mg dose of REVLIMID with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in

AUC and 50% decrease in C

max

. In the trials where the efficacy and safety were established for REVLIMID, the drug was administered without regard to food intake.

REVLIMID can be administered with or without food.

The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.

Distribution

In vitro [

14

C]-lenalidomide binding to plasma proteins is approximately 30%.

Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of REVLIMID 25 mg daily.

Elimination

The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.

Metabolism

Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5-

hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.

Excretion

Elimination is primarily renal. Following a single oral administration of [

14

C]-lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive

dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as lenalidomide in the urine within 24

hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds

the glomerular filtration rate.

Specific Populations

Renal Impairment: Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), 9 subjects with

moderate renal impairment (CLcr 30 to 49 mL/min), 4 subjects with severe renal impairment (CLcr < 30 mL/min), and 6 patients with end stage renal disease (ESRD)

requiring dialysis were administered a single 25 mg dose of REVLIMID. Three healthy subjects of similar age with normal renal function (CLcr > 80 mL/min) were

also administered a single 25 mg dose of REVLIMID. As CLcr decreased, half-life increased and drug clearance decreased linearly. Patients with moderate and severe

impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) had an

approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed

during a 4-hour hemodialysis session.

Adjust the starting dose of REVLIMID in patients with renal impairment based on the CLcr value [see Dosage and Administration (2.5)].

Hepatic Impairment: Mild hepatic impairment (defined as total bilirubin > 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did

not influence the disposition of lenalidomide. No pharmacokinetic data is available for patients with moderate to severe hepatic impairment.

Other Intrinsic Factors: Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM, MDS or MCL) did not have a

clinically relevant effect on lenalidomide clearance in adult patients.

Drug Interactions

Co-administration of a single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of REVLIMID

(25 mg).

Co-administration of REVLIMID (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the Cmax or

AUC of lenalidomide.

Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg),with REVLIMID (25 mg) did not significantly alter the pharmacokinetics of lenalidomide,

temsirolimus, or sirolimus (metabolite of temsirolimus).

In vitro studies demonstrated that REVLIMID is a substrate of P-glycoprotein (P-gp). REVLIMID is not a substrate of human breast cancer resistance protein (BCRP),

multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide

1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel

(OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.

Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with

UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with lenalidomide have not been conducted.

Reference ID: 4439576

30

13

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

14

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood

lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian

Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg,

based on body surface area) produced no parental toxicity and no adverse effects on fertility.

CLINICAL STUDIES

14.1 Multiple Myeloma

Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed MM:

A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of REVLIMID and low-dose dexamethasone

(Rd) given for 2 different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed MM patients who were not a candidate for

stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to

eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for a maximum of twelve 42-day cycles (72

weeks). For the purposes of this study, a patient who was < 65 years of age was not a candidate for SCT if the patient refused to undergo SCT therapy or the patient did

not have access to SCT due to cost or other reasons. Patients were stratified at randomization by age (≤75 versus >75 years), stage (ISS Stages I and II versus Stage III),

and country.

Patients in the Rd Continuous and Rd18 arms received REVLIMID 25 mg once daily on Days 1 to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily

on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22

of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic

anticoagulation with the most commonly used being aspirin.

The demographics and disease-related baseline characteristics of the patients were balanced among the 3 arms. In general, study subjects had advanced-stage disease.

Of the total study population, the median age was 73 in the 3 arms with 35% of total patients > 75 years of age; 59% had ISS Stage I/II; 41% had ISS stage III; 9% had

severe renal impairment (creatinine clearance [CLcr] < 30 mL/min); 23% had moderate renal impairment (CLcr > 30 to 50 mL/min; 44% had mild renal impairment

(CLcr > 50 to 80 mL/min). For ECOG Performance Status, 29% were Grade 0, 49% Grade 1, 21% Grade 2, 0.4% ≥ Grade 3.

The primary efficacy endpoint, progression-free survival (PFS), was defined as the time from randomization to the first documentation of disease progression as

determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group [IMWG] criteria or death due to any cause,

whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd

Continuous and MPT arms. The efficacy results are summarized in the table below. PFS was significantly longer with Rd Continuous than MPT: HR 0.72 (95% CI:

0.61-0.85 p <0.0001). A lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The

improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous

compared with MPT (75.1% versus 62.3%); with a complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first

response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm.

For the interim OS analysis with 03 March 2014 data cutoff, the median follow-up time for all surviving patients is 45.5 months, with 697 death events, representing

78% of prespecified events required for the planned final OS analysis (697/896 of the final OS events). The observed OS HR was 0.75 for Rd Continuous versus MPT

(95% CI = 0.62, 0.90).

Table 13: Overview of Efficacy Results – Study MM-020 (Intent-to-treat Population)

Rd Continuous

(N = 535)

Rd18

(N = 541)

MPT

(N = 547)

PFS – IRAC (months)

g

Number of PFS events 278 (52) 348 (64.3) 334 (61.1)

Median

a

PFS time, months (95% CI)

b

25.5 (20.7, 29.4) 20.7 (19.4, 22) 21.2 (19.3, 23.2)

HR [95% CI]

c

;

p

-value

d

Rd Continuous vs MPT 0.72 (0.61, 0.85);

<0.0001

Rd Continuous vs Rd18 0.70 (0.60, 0.82)

Rd18 vs MPT 1.03 (0.89, 1.20)

Overall Survival (months)

h

Number of Death events 208

(

38.9

)

228

(

42.1

)

261

(

47.7

)

Median

a

OS time, months

(

95% CI

)

b

58.9

(

56, NE

)

f

56.7

(

50.1, NE

)

48.5

(

44.2, 52

)

HR [95% CI]

c

Rd Continuous vs MPT 0.75 (0.62, 0.90)

Rd Continuous vs Rd18 0.91 (0.75, 1.09)

Rd18 vs MPT

0.83

(

0.69, 0.99

)

Res

p

onse Rate

e

–

IRAC, n (%)

g

CR 81

(

15.1

)

77

(

14.2

)

51

(

9.3

)

VGPR 152

(

28.4

)

154

(

28.5

)

103

(

18.8

)

PR 169 (31.6) 166 (30.7) 187 (34.2)

Overall response: CR, VGPR, or PR 402 (75.1) 397 (73.4) 341 (62.3)

CR = complete response; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee; M = melphalan;

NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response; R = REVLIMID; Rd

Reference ID: 4439576

31

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide; VGPR = very good partial response; vs

= versus.

a

The median is based on the Kaplan-Meier estimate.

b

The 95% Confidence Interval (CI) about the median.

c

Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms.

d

The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms.

e

Best assessment of response during the treatment phase of the study.

f

Including patients with no response assessment data or whose only assessment was “response not evaluable.”

g

Data cutoff date = 24 May 2013.

h

Data cutoff date = 3 March 2014.

Reference ID: 4439576

32

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Curves of Progression-free Survival Based on IRAC Assessment (ITT MM Population)

Between Arms Rd Continuous, Rd18 and MPT

Cutoff date: 24 May 2013

CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee; M = melphalan; P = prednisone;

R = REVLIMID; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide.

Reference ID: 4439576

33

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Curves of Overall Survival (ITT MM Population)

Between Arms Rd Continuous, Rd18 and MPT

Cutoff date: 03 Mar 2014

CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; M = melphalan; P = prednisone; R = REVLIMID; Rd Continuous = Rd given until

documentation of progressive disease; Rd18 = Rd given for ≤18 cycles; T = thalidomide.

Randomized, Placebo-Controlled Clinical Trials - Maintenance Following Auto-HSCT:

Two multicenter, randomized, double-blind, parallel group, placebo-controlled studies were conducted to evaluate the efficacy and safety of REVLIMID maintenance

therapy in the treatment of MM patients after auto-HSCT. In Maintenance Study 1, patients between 18 and 70 years of age who had undergone induction therapy

followed by auto-HSCT were eligible. Induction therapy must have occurred within 12 months. Within 90-100 days after auto-HSCT, patients with at least a stable

disease response were randomized 1:1 to receive either REVLIMID or placebo maintenance. In Maintenance Study 2, patients aged < 65 years at diagnosis who had

undergone induction therapy followed by auto-HSCT and had achieved at least a stable disease response at the time of hematologic recovery were eligible. Within 6

months after auto-HSCT, patients were randomized 1:1 to receive either REVLIMID or placebo maintenance. Patients eligible for both trials had to have CLcr

≥30 mL/minute.

In both studies, the REVLIMID maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles, could be increased to 15 mg once daily after 3 months

in the absence of dose-limiting toxicity, and treatment was to be continued until disease progression or patient withdrawal for another reason. The dose was reduced, or

treatment was temporarily interrupted or stopped, as needed to manage toxicity. A dose increase to 15 mg once daily occurred in 135 patients (58%) in Maintenance

Study 1, and in 185 patients (60%) in Maintenance Study 2.

The demographics and disease-related baseline characteristics of the patients were similar across the two studies and reflected a typical MM population after auto-

HSCT (see Table 14).

Reference ID: 4439576

34

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 14: Baseline Demographic and Disease-Related Characteristics – MM Maintenance Studies 1 and 2

Maintenance Study 1 Maintenance Study 2

REVLIMID

N = 231

Placebo

N = 229

REVLIMID

N = 307

Placebo

N = 307

Age (years)

Median 58 58 57.5 58.1

(Min, max) (29, 71) (39, 71) (22.7, 68.3) (32.3, 67)

Sex, n (%)

Male 121 (52) 129 (56) 169 (55) 181 (59)

Female 110 (48) 100 (44) 138 (45) 126 (41)

ISS Stage at Diagnosis,

n (%)

Stage I or II 120 (52) 131 (57) 232 (76) 250 (81)

Stage

I

62 (27) 85 (37) 128 (42) 143 (47)

Stage I

I

58 (25) 46 (20) 104 (34) 107 (35)

Stage III 39 (17) 35 (15) 66 (21) 46 (15)

Missing 72 (31) 63 (28) 9 (3) 11 (4)

CrCl at Post-auto-HSCT,

n (%)

< 50 mL/min

23 (10) 16 (7)

10 (3) 9 (3)

 50 mL/min

201 (87) 204 (89) 178 (58) 200 (65)

Missing 7 (3) 9 (4) 119 (39) 98 (32)

Data cutoff date = 1 March 2015.

The major efficacy endpoint of both studies was PFS defined from randomization to the date of progression or death, whichever occurred first; the individual studies

were not powered for an overall survival endpoint. Both studies were unblinded upon the recommendations of their respective data monitoring committees and after

surpassing the respective thresholds for preplanned interim analyses of PFS. After unblinding, patients continued to be followed as before. Patients in the placebo arm

of Maintenance Study 1 were allowed to cross over to receive REVLIMID before disease progression (76 patients [33%] crossed over to REVLIMID); patients in

Maintenance Study 2 were not recommended to cross over. The efficacy results are summarized in the following table. In both studies, the primary analysis of PFS at

unblinding was significantly longer with REVLIMID compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.27-0.54 p <0.001) and Maintenance Study 2 HR

0.50 (95% CI: 0.39-0.64 p <0.001). For both studies, PFS was updated with a cutoff date of 1 March 2015 as shown in the table and the following Kaplan Meier graphs.

With longer follow-up (median 72.4 and 86.0 months, respectively), the updated PFS analyses for both studies continue to show a PFS advantage for REVLIMID

compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.28-0.50) with median PFS of 68.6 months and Maintenance Study 2 HR 0.53 (95% CI: 0.44-0.64) with

median PFS of 46.3 months.

Descriptive analysis of OS data with a cutoff date of 1 February 2016 are provided in Table 15. Median follow-up time was 81.6 and 96.7 months for

Maintenance Study 1 and Maintenance Study 2, respectively. Median OS was 111.0 and 84.2 months for REVLIMID and placebo, respectively, for Maintenance

Study 1, and 105.9 and 88.1 months, for REVLIMID and placebo, respectively, for Maintenance Study 2.

Reference ID: 4439576

35

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 15: Progression-free Survival and Overall Survival from

Randomization in MM Maintenance Studies 1 and 2 (ITT Post-Auto-HSCT Population)

Maintenance Study 1 Maintenance Study 2

REVLIMID

N = 231

Placebo

N = 229

REVLIMID

N = 307

Placebo

N = 307

PFS at Unblinding

PFS Events n (%)

46 (20) 98 (43) 103 (34) 160 (52)

Median in months [95% CI]

33.9

[NE, NE]

19

[16.2, 25.6]

41.2

[38.3, NE]

23.0

[21.2, 28.0]

Hazard Ratio

[95% CI]

0.38

[0.27, 0.54]

0.50

[0.39, 0.64]

Log-rank Test p-value

<0.001 <0.001

PFS at Updated Analysis

1 March 2015 (Studies 1 and 2)

PFS Events n (%) 97 (42) 116 (51) 191 (62) 248 (81)

Median in months [95% CI]

68.6

[52.8, NE]

22.5

[18.8, 30.0]

46.3

[40.1, 56.6]

23.8

[21.0, 27.3]

Hazard Ratio

[95% CI]

0.38

[0.28, 0.50]

0.53

[0.44, 0.64]

OS at Updated Analysis

1 Feb 2016 (Studies 1 and 2)

OS Events n (%) 82 (35) 114 (50) 143 (47) 160 (52)

Median in months [95% CI]

111

[101.8, NE]

84.2

[71.0, 102.7]

105.9

[88.8, NE]

88.1

[80.7, 108.4]

Hazard Ratio

[95% CI]

0.59

[0.44, 0.78]

0.90

[0.72, 1.13]

Date of Unblinding in Maintenance Study 1 and 2 = 17 December 2009 and 7 July 2010, respectively.

Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; ITT = intent to treat; NE = not estimable;

PFS = progression-free survival.

PFS at time of unblinding for Maintenance Study 2 was based on assessment by an Independent Review Committee. All other PFS

analyses were based on assessment by investigator.

Note: The median is based on Kaplan-Meier estimate, with 95% CIs about the median overall PFS time. Hazard ratio is based on a

proportional hazards model stratified by stratification factors comparing the hazard functions associated with treatment arms

(REVLIMID:placebo).

Reference ID: 4439576

36

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Curves of Progression-free Survival from Randomization

(ITT Post-Auto-HSCT Population) in MM Maintenance Study 1 between REVLIMID and

Placebo Arms (Updated Cutoff Date 1 March 2015)

Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan-Meier;

PFS = progression-free survival; vs = versus.

Reference ID: 4439576

37

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Curves of Progression-free Survival from Randomization

(ITT Post-Auto-HSCT Population) in MM Maintenance Study 2 between

REVLIMID and Placebo Arms (Updated Cutoff Date 1 March 2015)

Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan-Meier; NE = not

estimable; PFS = progression-free survival; vs = versus.

Randomized, Open-Label Clinical Studies in Patients with MM After At Least One Prior Therapy

Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID. These multicenter, multinational, double-blind, placebo-

controlled studies compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with MM who had received at

least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm

3

, platelet counts ≥ 75,000/mm

3

, serum creatinine ≤ 2.5

mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL.

In both studies, patients in the REVLIMID/dexamethasone group took 25 mg of REVLIMID orally once daily on Days 1 to 21 and a matching placebo capsule once

daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both

treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.

The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was

to continue until disease progression.

In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were

allowed for toxicity [see Dosage and Administration (2.1)].

Table 16 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were

comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.

Reference ID: 4439576

38

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 16: Baseline Demographic and Disease-Related Characteristics – MM Studies 1 and 2

Study 1 Study 2

REVLIMID/Dex

N=177

Placebo/Dex

N=176

REVLIMID/Dex

N=176

Placebo/Dex

N=175

Patient Characteristics

Age (years)

Median

Min, Max

64

36, 86

62

37, 85

63

33, 84

64

40, 82

Sex

Male

Female

106 (60%)

71 (40%)

104 (59%)

72 (41%)

104 (59%)

72 (41%)

103 (59%)

72 (41%)

Race/Ethnicity

White

Other

141(80%)

36 (20%)

148 (84%)

28 (16%)

172 (98%)

4 (2%)

175 (100%)

0 (0%)

ECOG Performance

Status 0-1 157 (89%) 168 (95%) 150 (85%) 144 (82%)

Disease Characteristics

Multiple Myeloma Stage (Durie-Salmon)

I

II

III

3%

32%

64%

3%

31%

66%

6%

28%

65%

5%

33%

63%

β2-microglobulin (mg/L)

≤ 2.5 mg/L

> 2.5 mg/L

52 (29%)

125 (71%)

51 (29%)

125 (71%)

51 (29%)

125 (71%)

48 (27%)

127 (73%)

Number of Prior Therapies

1

≥ 2

38%

62%

38%

62%

32%

68%

33%

67%

Types of Prior Therapies

Stem Cell Transplantation 62% 61% 55% 54%

Thalidomide 42% 46% 30% 38%

Dexamethasone 81% 71% 66% 69%

Bortezomib 11% 11% 5% 4%

Melphalan 33% 31% 56% 52%

Doxorubicin 55% 51% 56% 57%

The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive

disease.

Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP.

The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both

studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in

REVLIMID/dexamethasone group and 31.6 months (95% CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2,

the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone

group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).

Reference ID: 4439576

39

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 17: TTP Results in MM Study 1 and Study 2

Study 1 Study 2

REVLIMID/Dex

N=177

Placebo/Dex

N=176

REVLIMID/Dex

N=176

Placebo/Dex

N=175

TTP

Events n

(

%

)

73

(

41

)

120

(

68

)

68

(

39

)

130

(

74

)

Median TTP in months [95% CI]

13.9

[9.5, 18.5]

4.7

[3.7, 4.9]

12.1

[9.5, NE]

4.7

[3.8, 4.8]

Hazard Ratio

[95% CI]

0.285

[0.210, 0.386]

0.324

[0.240, 0.438]

Log-rank Test p-value

3

<0.001 <0.001

Response

Complete Response (CR) n (%)

23 (13) 1 (1) 27 (15) 7 (4)

Partial Response (RR/PR) n (%)

84 (48) 33 (19) 77 (44) 34 (19)

Overall Response n (%)

107 (61) 34 (19) 104 (59) 41 (23)

p-value <0.001 <0.001

Odds Ratio [95% CI] 6.38

[3.95, 10.32]

4.72

[2.98, 7.49]

Kaplan-Meier Estimate of Time to Progression — MM Study 1

0 10 20 30

0

25

50

75

100

Revlimid/Dex

Placebo/Dex

Log Rank p < 0.001

HR (95% CI) = 0.285 (0.210-0.386)

Proportion of Subjects

Time to Progression (months)

Reference ID: 4439576

40

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Estimate of Time to Progression — MM Study 2

14.2 Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality

The efficacy and safety of REVLIMID were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31-33)

cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an

open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential

dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity [Dosage and Administration (2.2)].

This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs

within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm

3

, platelet counts ≥ 50,000/mm

3

, serum creatinine

≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was

permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in

Table 18.

Table 18: Baseline Demographic and Disease-Related Characteristics in the MDS Study

Overall

(N=148)

Age (years)

Median

Min, Max

71

37, 95

Gender n (%)

Male

Female

51

97

(34.5)

(65.5)

Race n (%)

White

Other

143

5

(96.6)

( 3.4)

Duration of MDS (years)

Median

Min, Max

2.5

0.1, 20.7

Del 5 (q31-33) Cytogenetic Abnormality n (%)

Yes

Other cytogenetic abnormalities

148

37

(100)

(25.2)

IPSS Score

a

n (%)

Low (0)

Intermediate-1 (0.5-1.0)

Intermediate-2 (1.5-2.0)

High (≥2.5)

Missing

55

65

6

2

20

(37.2)

(43.9)

( 4.1)

( 1.4)

(13.5)

FAB Classification

b

from central review n (%)

RA

RARS

RAEB

CMML

77

16

30

3

(52)

(10.8)

(20.3)

( 2)

a

IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1),

Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score =

(Marrow blast score + Karyotype score + Cytopenia score).

b

French-American-British (FAB) classification of MDS.

The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC

transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.

Reference ID: 4439576

41

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first

declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period

among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months

in the study.

RBC transfusion independence rates were unaffected by age or gender.

The dose of REVLIMID was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction

or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265

days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second

dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days;

range, 2-148 days).

14.3 Mantle Cell Lymphoma

A multicenter, single-arm, open-label trial of single-agent REVLIMID was conducted to evaluate the safety and efficacy of REVLIMID in patients with mantle cell

lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance ≥60 mL/min were given

REVLIMID at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥30 mL/min and <60 mL/min were given REVLIMID at a

dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received

prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have

documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed

disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute

neutrophil counts (ANC) ≥1500/ mm

3

, platelet counts ≥ 60,000/mm

3

, serum SGOT/AST or SGPT/ALT ≤3x upper limit of normal (ULN) unless there was documented

evidence of liver involvement by lymphoma, serum total bilirubin ≤1.5 x ULN except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma,

and calculated creatinine clearance (Cockcroft-Gault formula) ≥30 mL/min.

The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-

lymphoma therapy in the Mantle Cell Lymphoma trial.

Table 19: Baseline Disease-related Characteristics and Prior Anti –Lymphoma Therapy in

Mantle Cell Lymphoma Trial

Baseline Disease Characteristics and Prior Anti -

Lymphoma Treatment

Total Patients

(N=134)

ECOG Performance Status

a

n (%)

0

1

2

3

43 (32)

73 (54)

17 (13)

1 (<1)

Advanced MCL Stage, n (%)

III

IV

27 (20)

97 (72)

High or Intermediate MIPI Score

b

, n (%) 90 (67)

High Tumor Burden

c

, n (%) 77 (57)

Bulky Disease

d

, n (%) 44 (33)

Extranodal Disease, n (%) 101 (75)

Number of Prior Systemic Anti-Lymphoma

Therapies, n (%)

Median (range)

1

2

3

≥ 4

4 (2, 10)

0 (0)

29 (22)

34 (25)

71 (53)

Number of Subjects Who Received Prior Regimen

Containing, n (%):

Anthracycline/mitoxantrone

Cyclophosphamide

Rituximab

Bortezomib

133 (99)

134 (100)

Refractory to Prior Bortezomib, n (%) 81 (60)

Refractory to Last Prior Therapy, n (%) 74 (55)

Prior Autologous Bone Marrow or Stem Cell

Transplant, n (%)

39 (29)

a

ECOG = Eastern Cooperative Oncology Group.

b

MIPI = MCL International Prognostic Index.

c

High tumor burden is defined as at least one lesion that is ≥5 cm in diameter or 3 lesions that are ≥3 cm in diameter.

d

Bulky disease is defined as at least one lesion that is ≥7cm in the longest diameter.

The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic

scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is

defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable

patients who received at least one dose of study drug and are presented in Table 20. The median time to response was 2.2 months (range 1.8 to 13 months).

Reference ID: 4439576

42

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 20: Response Outcomes in the Pivotal Mantle Cell Lymphoma Trial

Response Analyses (N = 133) N (%) 95% CI

Overall Response Rate (IWRC) (CR + CRu +PR) 34 (26) (18.4, 33.9)

Complete Response (CR + CRu) 9 (7) (3.1, 12.5)

CR 1 (1)

CRu 8 (6)

Partial Response (PR) 25 (19)

Duration of Response (months) Median 95% CI

Duration of Overall Response (CR + CRu + PR) (N = 34) 16.6 (7.7, 26.7)

14.4 Follicular and Marginal Zone Lymphoma

The efficacy of REVLIMID with rituximab in patients with relapsed or refractory follicular and marginal zone lymphoma was evaluated in the AUGMENT

(NCT01938001) and MAGNIFY (NCT01996865) trials.

AUGMENT is a randomized, double-blind, multicenter trial (n=358) in which patients with relapsed or refractory follicular or marginal zone lymphoma were

randomized 1:1 to receive REVLIMID and rituximab or rituximab and placebo. AUGMENT included patients diagnosed with Grade 1, 2, or 3a follicular lymphoma,

who received at least 1 prior systemic therapy, were refractory or relapsed, not rituximab-refractory, had at least one measurable nodal or extranodal lesion by CT or

MRI scan, and had adequate bone marrow, liver, and renal function. Randomization was stratified by follicular versus marginal zone lymphoma, previous rituximab

therapy, and time since other anti-lymphoma therapy. In AUGMENT, REVLIMID was administered orally 20 mg once daily for Days 1 to 21 of repeating 28-day

cycles for a maximum of 12 cycles or until unacceptable toxicity. The dose of rituximab was 375 mg/m

2

every week in Cycle 1 (Days 1, 8, 15, and 22) and on Day 1 of

every 28-day cycle from Cycles 2 through 5. All dosage calculations for rituximab were based on the patient’s body surface area (BSA), using actual patient weight.

Dose adjustments for REVLIMID were allowed based on clinical and laboratory findings. A patient with moderate renal insufficiency (≥30 to <60 mL/minute) received

a lower REVLIMID starting dose of 10 mg daily on the same schedule. After 2 cycles, the REVLIMID dose could be increased to 15 mg once daily on Days 1 to 21 of

each 28-day cycle if the patient tolerated the medication.

MAGNIFY is an open-label, multicenter trial (n=232) in which patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma received 12

induction cycles of REVLIMID and rituximab. MAGNIFY included patients diagnosed with Grade 1, 2,3a, 3b follicular (including transformed), marginal zone, or

mantle cell lymphoma Stage I to IV who were previously treated for their lymphoma, had been refractory or had a relapse after their last treatment, had at least one

measurable nodal or extranodal lesion by CT or MRI scan, and had adequate bone marrow, liver, and renal function. Patients refractory to rituximab were also included.

The information from the subjects who received at least 1 dose of initial therapy in the first 12 induction cycles (n=222) in the MAGNIFY trial was included in the

evaluation of the efficacy of REVLIMID/rituximab in patients with relapsed or refractory follicular and marginal zone lymphoma. In MAGNIFY, REVLIMID 20 mg

was given on Days 1-21 of repeated 28-day cycles for up to 12 cycles or until unacceptable toxicity, progression, or withdrawal of consent. The dose of rituximab was

375 mg/m

2

every week in Cycle 1 (Days 1, 8, 15, and 22) and on Day 1 of every other 28-day cycle (Cycles 3,5,7,9, and 11) up to 12 cycles therapy. All dosage

calculations for rituximab were based on the patient BSA and actual weight. Dose adjustments were allowed based on clinical and laboratory findings.

The demographic and disease-related baseline characteristics in the AUGMENT and MAGNIFY trials are shown in the following table.

Table 21: Baseline Demographics and Disease-Related Characteristics of Patients with FL and MZL in AUGMENT and MAGNIFY Trials

Parameter

AUGMENT Trial MAGNIFY Trial

REVLIMID + Rituximab

(N=178)

Rituximab + Placebo

(Control Arm)

(N=180)

REVLIMID + Rituximab

(N=222)

Age (years)

Median (Max, Min) 64 (26, 86) 62 (35, 88) 65 (35, 91)

Age distribution, n (%)

<65 years 96 (54) 107 (59) 103 (46)

≥65 years 82 (46) 73 (41) 119 (54)

Sex, n (%)

Male 75 (42) 97 (54) 122 (55)

Female 103 (58) 83 (46) 100 (45)

Race

White 118 (66) 115 (64) 206 (93)

Other races 54 (30) 64 (36) 14 (6)

Not collected or reported 6 (3) 1 (0.6) 2 (1)

Body Surface Area (BSA,

m

2

)

Median (Max, Min) 1.8 (1.4, 3.1) 1.8 (1.3, 2.7) 2 (1.3, 2.6)

Disease Type FL or MZL

Follicular lymphoma 147 (83) 148 (82) 177 (80)

Marginal zone lymphoma 31 (17) 32 (18) 45 (20)

MZL subtype at diagnosis (investigator), n (%)

MALT 14 (45) 16 (50) 10 (22)

Nodal 8 (26) 10 (31) 25 (56)

Splenic 9 (29) 6 (19 10 (22)

FL stage at diagnosis (investigator), n (%)

FL Grade 1-2 125 (85) 123 (83) 149 (84)

FL Grade 3a 22 (15) 25 (17) 28 (16)

FLIPI score at baseline (calculated), n (%) Not Collected

Reference ID: 4439576

43

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Parameter

AUGMENT Trial MAGNIFY Trial

REVLIMID + Rituximab

(N=178)

Rituximab + Placebo

(Control Arm)

(N=180)

REVLIMID + Rituximab

(N=222)

Low risk (0,1) 52 (29) 67 (37)

Intermediate risk (2) 55 (31) 58 (32)

High risk (≥3) 69 (39) 54 (30)

Missing 2 (1) 1 (0.6)

ECOG score at baseline, n (%)

0 116 (65) 128 (71) 102 (46)

1 60 (34) 50 (28) 113 (51)

2 2 (1) 2 (1) 7 (3)

High tumor burden

b

at baseline, n (%)

Yes 97 (54) 86 (48) 148 (67)

No 81 (46) 94 (52) 74 (33)

Number of prior systemic antilymphoma

therapies

1 102 (57) 97 (54) 94 (42)

>1 76 (43) 83 (46) 128 (58)

Data Cutoff: 22 June 2018 (AUGMENT) and 1 May 2017 (MAGNIFY).

a

Patient had either 0 (n=2) or 1 prior systemic therapy.

b

Defined by GELF criteria.

ECOG = Eastern Cooperative Oncology Group; FLIPI = follicular lymphoma international prognostic index

In AUGMENT, efficacy was established in the intent-to-treat (ITT) population based on progression-free survival by Independent Review Committee using modified

2007 International Working Group response criteria. Efficacy results are summarized in Table 22.

Table 22: Efficacy Results for Patients in the AUGMENT Trial (ITT FL and MZL Population)

Parameter REVLIMID + Rituximab

(N=178)

Rituximab + Placebo

(N=180)

PFS

Patients with event, n (%) 68 (38.2) 115 (63.9)

Death 6 (8.8) 2 (1.7)

Progression of disease 62 (91.2) 113 (98.3)

PFS, median

a

[95% CI] (months) 39.4 [ 22.9, NE] 14.1 [11.4, 16.7]

HR

b

[95% CI] 0.46 [ 0.34, 0.62]

p-value

c

<0.0001

Objective response (CR+PR) , n(%)

[95% CI]

d

138 (77.5) [70.7, 83.4] 96 (53.3) [45.8, 60.8]

a

Median estimate is from Kaplan-Meier analysis.

b

hazard ratio and its CI were estimated from Cox proportional hazard model adjusting for the stratification 3: previous rituximab treatment

(yes, no), time since last antilymphoma therapy (≤ 2, > 2 years), and disease histology (FL, MZL).

c

p-value from log-rank test stratified by 3 factors noted above: previous rituximab treatment (yes, no), time since last antilymphoma therapy

(≤ 2, > 2 years), and disease histology (FL, MZL).

d

Exact confidence interval for binomial distribution.

Reference ID: 4439576

44

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Kaplan-Meier Curves of Progression-free Survival by IRC Assessment Between Arms in AUGMENT Trial (ITT FL and MZL Population)

SSuurrvvivivaall PPrroobbaabbilitilityy

1.1.00

0.0.88

0.0.66

0.0.44

0.0.22

0.0.00

2: Rituximab + Placebo

1: Rituximab + Lenalidomide

Log Rank p[a] <0.0001

HR (95% CI)[ a] = 0.46 ( 0.34, 0.62)

00 66 1212 1818 2424 3030 3636 4242

PrProoggrreessssiioonn-- ffrreeee SuSurrvviivvaall ((MM oonntthhss))

1 178 148 124 91 59 39 20 7 0

2

180 132 92 58 40 26 10 4 0

N umber of Subj ects at Risk

a = Stratification factors included: previous rituximab treatment (y/n), time since last anti-lymphoma therapy (≤2 years, >2years), and disease histology (FL or MZL).

CI = confidence interval; HR = hazard ratio; KM = Kaplan-Meier; PFS = progression-free survival

Follicular Lymphoma

In AUGMENT, the objective response by IRC assessment for patients with follicular lymphoma was 80% (118/147) [95% CI: 73%, 86%]) in REVLIMID with

rituximab arm compared to 55% (82/148) [95% CI: 47, 64] in control arm.

In MAGNIFY, the overall response by investigator assessment was 59% (104/177) [95% CI: 51, 66] for patients with follicular lymphoma. Median duration of response

was not reached with a median follow-up time of 7.9 months [95% CI: 4.6, 9.2].

Marginal Zone Lymphoma

In AUGMENT, the objective response by IRC assessment for patients with marginal zone lymphoma was 65% (20/31) [95% CI: 45%, 81%] in REVLIMID with

rituximab arm compared to 44% (14/32) [95% CI: 26%, 62%] in control arm.

In MAGNIFY, the overall response by investigator assessment was 51% (23/45) [95% CI: 36, 66] for patients with marginal zone lymphoma. Median duration of

response was not reached with a median follow-up time of 11.5 months [95% CI: 8.0, 18.9].

15 REFERENCES

1. OSHA Hazardous Drugs. OSHA [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

White and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink:

2.5 mg bottles of 28 (NDC 59572-402-28)

Reference ID: 4439576

45

4848

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

2.5 mg bottles of 100 (NDC 59572-402-00)

White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink:

5 mg bottles of 28 (NDC 59572-405-28)

5 mg bottles of 100 (NDC 59572-405-00)

Blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink:

10 mg bottles of 28 (NDC 59572-410-28)

10 mg bottles of 100 (NDC 59572-410-00)

Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink:

15 mg bottles of 21 (NDC 59572-415-21)

15 mg bottles of 100 (NDC 59572-415-00)

Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink.

20 mg bottles of 21 (NDC 59572-420-21)

20 mg bottles of 100 (NDC 59572-420-00)

White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink:

25 mg bottles of 21 (NDC 59572-425-21)

25 mg bottles of 100 (NDC 59572-425-00)

16.2 Storage

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature].

16.3 Handling and Disposal

Care should be exercised in the handling of REVLIMID. REVLIMID capsules should not be opened or broken. If powder from REVLIMID contacts the skin, wash the

skin immediately and thoroughly with soap and water. If REVLIMID contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.

1

Dispense no more than a 28-day supply.

Reference ID: 4439576

46

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved Patient labeling (Medication Guide)

Embryo-Fetal Toxicity

Advise patients that REVLIMID is contraindicated in pregnancy [see Boxed Warning and Contraindications (4.1)]. REVLIMID is a thalidomide analogue and can

cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

 Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.

 Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.

 Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception including at least 1

highly effective form, simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID.

Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s

vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

 Instruct patient to immediately stop taking REVLIMID and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her

menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

 Advise patient that if her healthcare provider is not available, she should call Celgene Customer Care Center at 1-888-423-5436 [see Warnings and Precautions (5.1)

and Use in Specific Populations (8.3)].

 Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4

weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

 Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

 All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 4 weeks following discontinuation of REVLIMID [see

Warnings and Precautions (5.1)].

REVLIMID REMS program

Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS program [see Warnings and

Precautions (5.2)].

 Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential

must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception

requirements [see Use in Specific Populations (8.3)].

 REVLIMID is available only from pharmacies that are certified in REVLIMID REMS program. Provide patients with the telephone number and website for

information on how to obtain the product.

Pregnancy Exposure Registry

Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy and that they can

contact the Pregnancy Exposure Registry by calling 1-888-423-5436 [see Use in Specific Populations (8.1)].

Hematologic Toxicity

Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warning and Warnings and Precautions (5.3)].

Venous and Arterial Thromboembolism

Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for

evaluation [see Boxed Warning and Warnings and Precautions (5.4)].

Increased Mortality in Patients with CLL

Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial

infarction, and cardiac failure [see Warnings and Precautions (5.5)].

Second Primary Malignancies

Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)].

Hepatotoxicity

Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare

provider for evaluation [see Warnings and Precautions (5.8)].

Severe Cutaneous Reactions Including Hypersensitivity Reactions

Inform patients of the potential for severe reactions including hypersensitivity, angioedema, Stevens-Johnson Syndrome, toxic epidermal necrolysis or drug reaction

with eosinophilia and systemic symptoms if they had such a reaction to thalidomide and report symptoms associated with these events to their healthcare provider for

evaluation [see Warnings and Precautions (5.9)].

Tumor Lysis Syndrome

Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation

[see Warnings and Precautions (5.10)].

Tumor Flare Reaction

Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation

[see Warnings and Precautions (5.11)].

Early Mortality in Patients with MCL

Inform patients with MCL of the potential for early death [see Warnings and Precautions (5.14)].

Reference ID: 4439576

47

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Dosing Instructions

Inform patients how to take REVLIMID [see Dosage and Administration (2)]

 REVLIMID should be taken once daily at about the same time each day,

 REVLIMID may be taken either with or without food.

 The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.

 Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours

have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take

2 doses to make up for the one that they missed.

Manufactured for: Celgene Corporation

86 Morris Avenue

Summit, NJ 07901

REVLIMID

®

and REVLIMID REMS

®

are registered trademarks of Celgene Corporation.

Pat. www.celgene.com/therapies

RevPlyPI.026/MG.026

Reference ID: 4439576

48

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

MEDICATION GUIDE

REVLIMID

®

(rev-li-mid)

(lenalidomide)

capsules

What is the most important information I should know about REVLIMID?

Before you begin taking REVLIMID, you must read and agree to all of the instructions in the REVLIMID

REMS

®

program. Before prescribing REVLIMID, your healthcare provider will explain the REVLIMID

REMS program to you and have you sign the Patient-Physician Agreement Form.

REVLIMID may cause serious side effects including:

• Possible birth defects (deformed babies) or death of an unborn baby. Females who are

pregnant or who plan to become pregnant must not take REVLIMID.

REVLIMID is similar to the medicine thalidomide. We know thalidomide can cause severe life-

threatening birth defects. REVLIMID has not been tested in pregnant females. REVLIMID has

harmed unborn animals in animal testing.

Females must not get pregnant:

o For at least 4 weeks before starting REVLIMID

o While taking REVLIMID

o During any breaks (interruptions) in your treatment with REVLIMID

o For at least 4 weeks after stopping REVLIMID

Females who can become pregnant:

o Will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is

regular, or every 2 weeks if your menstrual cycle is irregular.

o If you miss your period or have unusual bleeding, you will need to have a pregnancy test and

receive counseling.

o Must agree to use two acceptable forms of birth control at the same time, for at least 4 weeks

before, while taking, during any breaks (interruptions) in your treatment, and for at least 4

weeks after stopping REVLIMID.

o Talk with your healthcare provider to find out about options for acceptable forms of birth control

that you may use to prevent pregnancy before, during, and after treatment with REVLIMID.

o If you had unprotected sex or if you think your birth control has failed, stop taking REVLIMID

immediately and call your healthcare provider right away.

If you become pregnant while taking REVLIMID, stop taking it right away and call your

healthcare provider. If your healthcare provider is not available, you can call Celgene Customer

Care Center at 1-888-423-5436. Healthcare providers and patients should report all cases of

pregnancy to:

o FDA MedWatch at 1-800-FDA-1088, and

o Celgene Corporation at 1-888-423-5436

There is a pregnancy exposure registry that monitors the outcomes of females who take REVLIMID

during pregnancy, or if their male partner takes REVLIMID and they are exposed during

pregnancy. You can enroll in this registry by calling Celgene Corporation at the phone number

listed above.

REVLIMID can pass into human semen:

o Males, including those who have had a vasectomy, must always use a latex or synthetic

condom during any sexual contact with a pregnant female or a female that can become

pregnant while taking REVLIMID, during any breaks (interruptions) in your treatment with

REVLIMID, and for up to 4 weeks after stopping REVLIMID.

o Do not have unprotected sexual contact with a female who is or could become pregnant. Tell

your healthcare provider if you do have unprotected sexual contact with a female who is or

could become pregnant.

o Do not donate sperm while taking REVLIMID, during any breaks (interruptions) in your

treatment, and for 4 weeks after stopping REVLIMID. If a female becomes pregnant with your

sperm, the baby may be exposed to REVLIMID and may be born with birth defects.

Men, if your female partner becomes pregnant, you should call your healthcare provider

ri

g

ht awa

y

.

Reference ID: 4439576

49

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

• Low white blood cells (neutropenia) and low platelets (thrombocytopenia). REVLIMID causes

low white blood cells and low platelets in most people. You may need a blood transfusion or certain

medicines if your blood counts drop too low. Your healthcare provider should check your blood

counts often especially during the first several months of treatment with REVLIMID, and then at

least monthly. Tell your healthcare provider if you develop any bleeding or bruising, during

treatment with REVLIMID.

• Blood clots. Blood clots in the arteries, veins, and lungs happen more often in people who take

REVLIMID. This risk is even higher for people with multiple myeloma who take the medicine

dexamethasone with REVLIMID. Heart attacks and strokes also happen more often in people who

take REVLIMID with dexamethasone. To reduce this increased risk, most people who take

REVLIMID will also take a blood thinner medicine.

Before taking REVLIMID, tell your healthcare provider:

o If you have had a blood clot in the past

o If you have high blood pressure, smoke, or if you have been told you have a high level of fat in

your blood (hyperlipidemia)

o About all the medicines you take. Certain other medicines can also increase your risk for

blood clots

Call your healthcare provider or get medical help right away if you get any of the following

during treatment with REVLIMID:

 Signs or symptoms of a blood clot in the lung, arm, or leg may include: shortness of

breath, chest pain, or arm or leg swelling

 Signs or symptoms of a heart attack may include: chest pain that may spread to the

arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath,

feeling sick or vomiting

 Signs or symptoms of stroke may include: sudden numbness or weakness, especially

on one side of the body, severe headache or confusion, or problems with vision, speech,

or balance

What is REVLIMID?

REVLIMID is a prescription medicine, used to treat adults with:

• multiple myeloma (MM)

o in combination with the medicine dexamethasone, or

o as maintenance treatment after autologous hematopoietic stem cell transplantation (a type of

stem cell transplant that uses your own stem cells)

• a condition called myelodysplastic syndromes (MDS). REVLIMID is for the type of MDS with a

chromosome problem where part of chromosome 5 is missing. This type of MDS is known as

deletion 5q MDS. People with this type of MDS may have low red blood cell counts that require

treatment with blood transfusions.

• mantle cell lymphoma (MCL) when the disease comes back or becomes worse after treatment with

2 prior medicines, one of which included bortezomib. MCL is a cancer of a type of white blood cell

called lymphocytes that are in the lymph nodes.

• follicular lymphoma (FL) or marginal zone lymphoma (MZL)

o in combination with a rituximab product, and

o who have previously been treated for their FL or MZL

FL and MZL are types of cancer of white blood cells called B-cell lymphocytes that are found in the

lymph nodes and spleen.

REVLIMID should not be used to treat people who have chronic lymphocytic leukemia (CLL) unless

they are participants in a controlled clinical trial.

It is not known if REVLIMID is safe and effective in children.

Who should not take REVLIMID?

Do not take REVLIMID if you:

• are pregnant, plan to become pregnant, or become pregnant during treatment with

REVLIMID. See “What is the most important information I should know about REVLIMID?”

• are allergic to lenalidomide or any of the ingredients in REVLIMID. See the end of this Medication

Guide for a complete list of in

g

redients in REVLIMID.

Reference ID: 4439576

50

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

What should I tell my healthcare provider before taking REVLIMID?

Before you take REVLIMID, tell your healthcare provider about all of your medical conditions,

including if you:

• have liver problems

• have kidney problems or receive kidney dialysis treatment

• have thyroid problems

• have had a serious skin rash with thalidomide treatment. You should not take REVLIMID.

• are lactose intolerant. REVLIMID contains lactose.

• are breastfeeding. Do not breastfeed during treatment with REVLIMID. It is not known if

REVLIMID passes into your breast milk and can harm your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. REVLIMID and other medicines may affect each

other, causing serious side effects. Talk with your healthcare provider before taking any new

medicines.

Know the medicines

y

ou take. Keep a list of them to show

y

our healthcare provider and pharmacist.

How should I take REVLIMID?

• Take REVLIMID exactly as prescribed and follow all the instructions of the REVLIMID REMS

program

• Swallow REVLIMID capsules whole with water 1 time a day. Do not open, break, or chew your

capsules.

• REVLIMID may be taken with or without food.

• Take REVLIMID at about the same time each day.

• Do not open or break REVLIMID capsules or handle them any more than needed.

o If powder from the REVLIMID capsule comes in contact with your skin, wash the skin right

away with soap and water.

o If powder from the REVLIMID capsule comes in contact with the inside of your eyes, nose, or

mouth, flush well with water.

• If you miss a dose of REVLIMID and it has been less than 12 hours since your regular time, take it

as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not

take 2 doses at the same time.

• If

y

ou take too much REVLIMID, call

y

our healthcare provider ri

g

ht awa

y

.

What should I avoid while taking REVLIMID?

• See “What is the most important information I should know about REVLIMID?”

• Females: Do not get pregnant and do not breastfeed while taking REVLIMID.

• Males: Do not donate sperm.

• Do not share REVLIMID with other people. It may cause birth defects and other serious

problems.

• Do not donate blood while you take REVLIMID, during any breaks (interruptions) in your

treatment, and for 4 weeks after stopping REVLIMID. If someone who is pregnant gets your

donated blood, her bab

y

ma

y

be exposed to REVLIMID and ma

y

be born with birth defects.

What are the possible side effects of REVLIMID?

REVLIMID can cause serious side effects, including:

• See “What is the most important information I should know about REVLIMID?”

• Increased risk of death in people who have chronic lymphocytic leukemia (CLL). People with

CLL who take REVLIMID have an increased risk of death compared with people who take the

medicine chlorambucil. REVLIMID may cause you to have serious heart problems that can lead to

death, including atrial fibrillation, heart attack, or heart failure. You should not take REVLIMID if you

have CLL unless you are participating in a controlled clinical trial.

• Risk of new cancers (malignancies). An increase in new (second) cancers has happened in

patients who received REVLIMID and melphalan, or a blood stem cell transplant, including certain

blood cancers, such as acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS)

and certain other types of cancers of the skin and other organs. Talk with your healthcare provider

about your risk of developing new cancers if you take REVLIMID. Your healthcare provider will

check

y

ou for new cancers durin

g y

our treatment with REVLIMID.

Reference ID: 4439576

51

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

• Severe liver problems, including liver failure and death. Your healthcare provider should do

blood tests to check your liver function during your treatment with REVLIMID. Tell your healthcare

provider right away if you develop any of the following symptoms of liver problems:

o yellowing of your skin or the white part of

your eyes (jaundice)

o dark or brown (tea-colored) urine

o pain on the upper right side of your stomach

area (abdomen)

o bleeding or bruising more easily than

normal

o

feelin

g

ver

y

tired

• Severe skin reactions including severe allergic reactions can happen with REVLIMID and may

cause death. Call your healthcare provider right away if you develop any of these signs or

symptoms of a severe allergic reaction or severe skin reaction during treatment with REVLIMID:

o swelling of your face, eyes, lips, tongue,

throat

o trouble swallowing

o trouble breathin

g

o skin rash, hives, or peeling of your skin

o blisters

o rash with fever and or swollen glands

• Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can

cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and

sometimes death. Your healthcare provider may do blood tests to check you for TLS.

• Worsening of your tumor (tumor flare reaction). Tell your healthcare provider if you get any of

these symptoms of tumor flare reaction while taking REVLIMID: tender swollen lymph nodes, low

grade fever, pain, or rash.

Your healthcare provider may tell you to decrease your dose, temporarily stop or permanently stop

taking REVLIMID if you develop certain serious side effects during treatment with REVLIMID.

• Thyroid problems. Your healthcare provider may check your thyroid function before you start

taking REVLIMID and during treatment with REVLIMID.

• Risk of Early Death in MCL. In people who have Mantle Cell Lymphoma (MCL), there may be a

risk of dying sooner (early death) when taking REVLIMID. Talk with your healthcare provider about

any concerns and possible risk factors.

The most common side effects of REVLIMID include:

 diarrhea

 rash

 nausea

 constipation

 tiredness or weakness

 fever

 itching

 swelling of your arms,

hands, legs, feet and skin

 sleep problems (insomnia)

 headache

 muscle cramps or spasms

 shortness of breath

 cough, sore throat, and

other symptoms of a cold

 upper respiratory tract infection or

bronchitis

 inflammation of the stomach and

intestine (“stomach flu”)

 nose bleed

 shaking or trembling (tremor)

 joint aches

 pain in your back or stomach-area

(

abdomen

)

These are not all the possible side effects of REVLIMID.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-

FD

A

-1088.

How should I store REVLIMID?

• Store REVLIMID at room temperature between 68°F to 77°F (20°C to 25°C).

• Return any unused REVLIMID to Celgene or your healthcare provider.

Keep REVLIMID and all medicines out of the reach of children.

General information about the safe and effective use of REVLIMID.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do

not take REVLIMID for conditions for which it was not prescribed. Do not give REVLIMID to other

people, even if they have the same symptoms you have. It may harm them and may cause birth

defects.

If you would like more information, talk with your healthcare provider. You can ask your healthcare

provider or pharmacist for information about REVLIMID that is written for health professionals.

What are the in

g

redients in REVLIMID?

Reference ID: 4439576

52

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Active ingredient: lenalidomide

Inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and

magnesium stearate.

The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink.

The 2.5 and 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide

and black ink.

The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.

The 20 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black

ink.

Manufactured for: Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901

REVLIMID

®

and REVLIMID REMS

®

are registered trademarks of Celgene Corporation.

For more information, call 1-888-423-5436 or go to www.CelgeneRiskManagement.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: May 2019

Reference ID: 4439576

53

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda