Revlimid (Lenalidomide) capsule
Celgene Corporation

Celgene Corporation
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;2;5;mg
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;5;mg
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;10;mg
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;15;mg
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;20;mg
Revlimid
Lenalidomide
LENALIDOMIDE
LENALIDOMIDE
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
REV;25;mg

Warnings and Precautions (5.1, 5.2)

8/2021

Warnings and Precautions (5.1, 5.11)

5/2022

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 Lenalidomide REMS program (5.2).

Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the REMS Call Center at 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)].

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 Lenalidomide 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).

1 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).

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

  • 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 (2.6).
  • For concomitant therapy doses, see Full Prescribing Information (2.1, 2.4, 14.1, 14.4).

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

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 below 2.5 mg daily

  For each subsequent drop below 30,000/mcL

Interrupt REVLIMID treatment

  Return to at least 30,000/mcL

Resume REVLIMID at next lower dose. Do not dose below 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 1,000/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 treatment

  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 1,000/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

Interrupt REVLIMID treatment, follow CBC weekly

  Return to at least 30,000/mcL

Resume REVLIMID at next lower dose, continuously for Days 1-28 of repeated 28-day cycle

  If at the 5 mg daily dose,
  For a subsequent drop below 30,000/mcL

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

Resume REVLIMID at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle

Absolute Neutrophil counts (ANC)

Neutropenia in MM

  When Neutrophils

Recommended Course

  Fall below 500/mcL

Interrupt REVLIMID treatment, follow CBC weekly

  Return to at least 500/mcL

Resume REVLIMID at next lower dose, continuously for Days 1-28 of repeated 28-day cycle

  If at 5 mg daily dose,
  For a subsequent drop below 500/mcL

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

2.2 Recommended Dosage for Myelodysplastic Syndromes

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 treatment

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 treatment

If baseline is at least 60,000/mcL and returns to at least 50,000/mcL

Resume REVLIMID at 5 mg daily

If baseline is below 60,000/mcL and returns to at least 30,000/mcL

Resume REVLIMID at 5 mg daily

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 with platelet transfusions

Interrupt REVLIMID treatment

Return to at least 30,000/mcL (without hemostatic failure)

Resume REVLIMID at 5 mg daily

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 with platelet transfusions

Interrupt REVLIMID treatment

Return to at least 30,000/mcL (without hemostatic failure)

Resume REVLIMID at 2.5 mg daily

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 treatment

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 treatment

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 associated with fever (at least 38.5°C)

Interrupt REVLIMID treatment

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 associated with fever (at least 38.5°C)

Interrupt REVLIMID treatment

Return to at least 500/mcL

Resume REVLIMID at 2.5 mg daily

2.3 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 Recommended Course

Fall below 50,000/mcL

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 below 5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in MCL

When Neutrophils Recommended Course

Fall below 1,000/mcL for at least 7 days
OR
Falls below 1,000/mcL with an associated temperature at least 38.5°C
OR
Falls below 500/mcL

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

2.4 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 Recommended Course

Fall below 50,000/mcL

Interrupt REVLIMID treatment and follow CBC weekly.

Return to at least 50,000/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.

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in FL or MZL

When Neutrophils Recommended Course

Fall below 1,000/mcL for at least 7 days
OR
Falls below 1,000/mcL with an associated temperature at least 38.5°C
OR
Falls below 500/mcL

Interrupt REVLIMID treatment and follow CBC weekly.

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.

2.5 Dosage Modifications for Non-Hematologic Adverse Reactions

For non-hematologic 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.

Permanently discontinue REVLIMID for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.9, 5.15)].

2.6 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.

2.7 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

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

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)].

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 (5.9, 5.15)].

5 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).
  • Severe Cutaneous Reactions: Discontinue REVLIMID for severe reactions (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, including fatal 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).
  • Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue REVLIMID for angioedema and anaphylaxis (5.15).

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 Lenalidomide 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 and for up to 4 weeks after discontinuing REVLIMID [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 Lenalidomide 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 Lenalidomide REMS program.

Required components of the Lenalidomide REMS program include the following:

  • Prescribers must be certified with the Lenalidomide 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 Lenalidomide REMS program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

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

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 patients 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.

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

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. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5)].

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 are 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), including fatal reactions, have 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/rituximab arm 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. In a separate MCL phase 2 trial, one case of TFR resulted in a fatal outcome.

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 109/L).

5.15 Hypersensitivity

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for angioedema and anaphylaxis [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS

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

  • 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 Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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*
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

Body System
Adverse Reaction

All Adverse Reactionsa

Grade 3/4 Adverse Reactionsb

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)

  Pyrexiac

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 painc

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%

Infections and infestations

  Bronchitisc

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 infectionc% f

69 (13)

53 ( 10)

31 ( 6)

< 1%

8 ( 1)

< 1%

  Pneumoniac@

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)

  Cellulitisc

< 5%

< 5%

< 5%

8 ( 2)

< 1%

< 1%

  Sepsisc@

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 disordersd

  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%

  Dyspneac,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)

  Gout 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 thrombosisc% 

55 (10)

39 ( 7)

22 ( 4)

30 ( 6)

20 ( 4)

15 ( 3)

  Hypotensionc% 

51 (10)

35 ( 6)

36 ( 7)

11 ( 2)

8 ( 1)

6 ( 1)

Injury, Poisoning, and Procedural Complications

  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 subcapsular 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 fibrillationc

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 carcinomac e

< 5%

< 5%

< 5%

8 ( 2)

< 1%

0 ( 0)

  Basal cell carcinomac e,f

< 5%

< 5%

< 5%

< 1%

< 1%

0 ( 0)

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.

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*
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]):
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

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)

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)