`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg (3).
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`Pregnancy (Boxed Warnings, 4.1, 5.1, 8.1).
`Demonstrated hypersensitivity to lenalidomide (4.2, 5.5).
`
` 
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`Allergic Reactions, including fatalities: Hypersensitivity, angioedema,
`Stevens-Johnson syndrome, toxic epidermal necrolysis; discontinue
`REVLIMID if reactions are suspected. Do not resume REVLIMID if
`these reactions are verified (5.5).
`Tumor lysis syndrome (TLS) including fatalities: Monitor patients at
`risk of TLS (i.e., those with high tumor burden) and take appropriate
`precautions (5.6).
`Tumor flare reaction: Serious tumor flare reactions have occurred
`during investigational use of REVLIMID for chronic lymphocytic
`leukemia and lymphoma (5.7, 6.3).
`Hepatotoxicity: Hepatic failure including fatalities; monitor liver
`function. Stop REVLIMID and evaluate if hepatotoxicity is suspected
`(5.8).
`Second Primary Malignancies (SPM): Higher incidences of SPM were
`observed in controlled trials of patients with multiple myeloma receiving
`REVLIMID (5.9).
`-------------------------------ADVERSE REACTIONS------------------------------
` MM: Most common adverse reactions (≥20%) include fatigue,
`neutropenia, constipation, diarrhea, muscle cramp, anemia, pyrexia,
`peripheral edema, nausea, back pain, upper respiratory tract infection,
`dyspnea, dizziness, thrombocytopenia, tremor and rash (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 (6.2).
` MCL: Most common adverse reactions (≥15%) include neutropenia,
`thrombocytopenia, fatigue, diarrhea, anemia, nausea, cough, pyrexia,
`rash, dyspnea, pruritus, constipation, peripheral edema and leukopenia
`(6.3).
`To report SUSPECTED ADVERSE REACTIONS or embryo-fetal
`exposure: contact Celgene Corporation at 1-888-423-5436 or FDA at
`1-800-332-1088 or www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
`
`
`
`
`
`
`
`
`
` 
`
`
`
`
`
` 
`
`
`
`
`
`Digoxin: Periodic monitoring of digoxin plasma levels is recommended
`due to increased Cmax and AUC with concomitant REVLIMID therapy
`(7.1).
`Patients taking concomitant therapies such as erythropoietin stimulating
`agents or estrogen containing therapies, may have an increased risk of
`venous thromboembolism (VTE) (7.3).
`
`Nursing Mothers: Discontinue drug or nursing taking into consideration
`importance of drug to the mother (8.3).
`Patients with Renal Insufficiency: Adjust the starting dose of with
`moderate or severe renal impairment and on dialysis (2.4).
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 06/2013
`
`
`
`
`
`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 US Approval: 2005
`
`
`
`
`
`
`WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC
`TOXICITY, and VENOUS 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 (5.2).
`REVLIMID is available only through a restricted distribution program
`called the REVLIMID REMSTM program (formerly known as the
`“RevAssist® program”) (5.2, 17).
`HEMATOLOGIC TOXICITY. REVLIMID can cause significant
`neutropenia and thrombocytopenia (5.3).
`
`For patients with del 5q myelodysplastic syndromes, monitor
`complete blood counts weekly for the first 8 weeks and monthly
`thereafter (5.3).
`VENOUS THROMBOEMBOLISM
`Significantly increased risk of deep vein thrombosis (DVT) and
`pulmonary embolism (PE) in patients with multiple myeloma
`receiving REVLIMID with dexamethasone (5.4).
`
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`Boxed Warning
`
`
`
`
`
`
`
`02/13
`Indication and Usage (1.3)
`
`
`
`
`
`06/13
`Dosage and Administration (2.1, 2.2, 2.3, 2.4)
`
`
`06/13
`Contraindications (4)
`
`
`
`
`
`
`02/13
`Warnings and Precautions (5.1, 5.2)
`
`
`
`
`02/13
`Warnings and Precautions (5.3, 5.4, 5.7, 5.8)
`
`
`06/13
`
`
`
`---------------------------INDICATIONS AND USAGE----------------------------
`
`REVLIMID is a thalidomide analogue indicated for the treatment of patients
`with:
` Multiple myeloma (MM), in combination with dexamethasone, in
`patients who have received at least one prior therapy (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).
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
` 
`
` MM: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles.
`Recommended dose of dexamethasone is 40 mg once daily on Days 1-4,
`9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and
`then 40 mg/day orally on Days 1-4 every 28 days (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).
`Continue or modify dosing based on clinical and laboratory findings
`(2.1, 2.2).
`Renal impairment: Adjust starting dose in patients with moderate or
`severe renal impairment and on dialysis (CLcr<60 mL/min) (2.4).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3319577
`
`

`

`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing mothers
`8.4 Pediatric use
`8.5 Geriatric use
`8.6 Females of Reproductive Potential and Males
`8.7 Renal Impairment
`8.8 Hepatic 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
`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
`
`
`
`FULL PRESCRIBING INFORMATION CONTENTS*
`WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC
`TOXICITY, and VENOUS THROMBOEMBOLISM
`1
`INDICATIONS AND USAGE
`
`1.1 Multiple Myeloma
`
`1.2 Myelodysplastic Syndromes
`
`1.3 Mantle Cell Lymphoma
`2 DOSAGE AND ADMINISTRATION
`2.1 Multiple Myeloma
`2.2 Myelodysplastic Syndromes
`2.3 Mantle Cell Lymphoma
`2.4 Starting Dose for Renal Impairment in MM, MDS or MCL
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`4.1 Pregnancy
`4.2 Allergic Reactions
`5 WARNINGS AND PRECAUTIONS
`5.1 Embryo-Fetal Toxicity
`5.2 REVLIMID REMS™ program
`5.3 Hematologic Toxicity
`5.4 Venous Thromboembolism
`5.5 Allergic Reactions
`5.6 Tumor Lysis Syndrome
`5.7 Tumor Flare Reaction
`5.8 Hepatotoxicity
`5.9 Second Primary Malignancies
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience in Multiple Myeloma
`6.2 Clinical Trials Experience in Myelodysplastic Syndromes
`6.3 Clinical Trials Experience in Mantle Cell Lymphoma
`6.4 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Digoxin
`7.2 Warfarin
`7.3 Concomitant Therapies That May Increase the Risk of Thrombosis
`
`Reference ID: 3319577
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS 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 REMSTM program (formerly known as the “RevAssist®” 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 Thromboembolism
`REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients
`with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be
`observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms
`such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet
`therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take
`prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and
`Precautions (5.4)].
`
`
`
`INDICATIONS AND USAGE
`
` 1
`
`
`1.1 Multiple Myeloma
`REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at
`least one prior therapy.
`1.2 Myelodysplastic Syndromes
`REVLIMID is indicated for the treatment of 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 patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior
`therapies, one of which included bortezomib.
`
` 2
`
`
`DOSAGE AND ADMINISTRATION
`REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed
`whole with water. The capsules should not be opened, broken, or chewed.
`2.1 Multiple Myeloma
`The recommended starting dose of REVLIMID is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of
`dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily
`orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.
`Dose Adjustments for Hematologic Toxicities During Multiple Myeloma 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 in MM
`
`
`When Platelets
`Fall to <30,000/mcL
`
`Return to ≥30,000/mcL
`
`Reference ID: 3319577
`
`Recommended Course
`Interrupt REVLIMID treatment, follow CBC
`weekly
`Restart REVLIMID at 15 mg daily
`
`

`

`
`
`For each subsequent drop <30,000/mcL
`Return to ≥30,000/mcL
`
`Absolute Neutrophil counts (ANC)
`Neutropenia in MM
`When Neutrophils
`Fall to <1000/mcL
`
`Return to ≥1,000/mcL and neutropenia is the only toxicity
`Return to ≥1,000/mcL and if other toxicity
`For each subsequent drop <1,000/mcL
`Return to ≥1,000/mcL
`
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg less than the
`previous dose. Do not dose below 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment, add G-CSF,
`follow CBC weekly
`Resume REVLIMID at 25 mg daily
`Resume REVLIMID at 15 mg daily
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg less than the
`previous dose. Do not dose below 5 mg daily
`
`
`Other Grade 3 / 4 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.
`
`Starting Dose Adjustment for Renal Impairment in MM:
`
`See Section 2.4.
`
`2.2 Myelodysplastic Syndromes
`The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings.
`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 ≥100,000/mcL
`When Platelets
`Fall to <50,000/mcL
`Return to ≥50,000/mcL
`If baseline <100,000/mcL
`When Platelets
`Fall to 50% of the baseline value
`If baseline ≥60,000/mcL and
`returns to ≥50,000/mcL
`If baseline <60,000/mcL and
`returns to ≥30,000/mcL
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`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
`<30,000/mcL or <50,000/mcL
`Interrupt REVLIMID treatment
`with platelet transfusions
`Return to ≥30,000/mcL
`(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
`<30,000/mcL or <50,000/mcL
`with platelet transfusions
`Return to ≥30,000/mcL
`(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
`
`Resume REVLIMID at 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`Resume REVLIMID at 2.5 mg daily
`
`Reference ID: 3319577
`
`

`

`
`
`
`
`If baseline ANC ≥1,000/mcL
`When Neutrophils
`Fall to <750/mcL
`Return to ≥1,000/mcL
`If baseline ANC <1,000/mcL
`When Neutrophils
`Fall to <500/mcL
`Return to ≥500/mcL
`
`
`If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS
`
`
`When Neutrophils
`<500/mcL for ≥7 days or <500/mcL
`associated with fever (≥38.5°C)
`Resume REVLIMID at 5 mg daily
`Return to ≥500/mcL
`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
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`When Neutrophils
`<500/mcL for ≥7 days or <500/mcL
`associated with fever (≥38.5°C)
`Return to ≥500/mcL
`
`Resume REVLIMID at 2.5 mg daily
`
`
`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.
`
`Starting Dose Adjustment for Renal Impairment in MDS:
`
`See Section 2.4.
`
`2.3 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 to <50,000/mcL
`
`
`Return to ≥50,000/mcL
`
`
`
`Absolute Neutrophil counts (ANC)
`
`Neutropenia during treatment in MCL
`When Neutrophils
`Fall to <1000/mcL for at least 7 days
`OR
`Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C
`OR
`Falls to < 500 /mcL
`
`Return to ≥1,000/mcL
`
`
`
`Reference ID: 3319577
`
`Recommended Course
`Interrupt REVLIMID treatment and follow
`CBC weekly
`
`Resume REVLIMID at 5 mg less than the
`previous dose. Do not dose below 5 mg daily
`
`
`Recommended Course
`Interrupt REVLIMID treatment and follow
`CBC weekly
`
`
`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.
`
`Starting Dose Adjustment for Renal Impairment in MCL:
`
`See Section 2.4.
`
`2.4 Starting Dose for Renal Impairment in MM, MDS or MCL
`
`Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide
`appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in
`patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with
`CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than
`7 mL/min have not been studied. The recommendations for initial starting doses for patients with MM, MDS or MCL are as follows:
`
`
`Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MM, MDS or MCL
`
`
`
`Category
`
`Renal Function (Cockcroft-
`Gault)
`CLcr 30-60 mL/min
`
`Moderate Renal
`Impairment
`Severe Renal Impairment CLcr < 30 mL/min (not
`requiring dialysis)
`CLcr < 30 mL/min (requiring
`dialysis)
`
`End Stage Renal Disease
`
`Dose in MM or MCL
`
`Dose in MDS
`
`10 mg
`Every 24 hours
`15 mg
`Every 48 hours
`5 mg
`Once daily. On dialysis
`days, administer the dose
`following dialysis.
`
`5 mg
`Every 24 hours
`2.5 mg
`Every 24 hours
`2.5 mg
`Once daily. On dialysis days,
`administer the dose following
`dialysis.
`
`
`After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described
`elsewhere (see section 2).
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
`REVLIMID 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules will be supplied through the REVLIMID REMS™ program.
`
`REVLIMID is available in the following capsule strengths:
`
`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
`
`
`
`CONTRAINDICATIONS
`
` 4
`
`
`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 hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].
`4.2 Allergic Reactions
`
`REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic
`epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.5)].
`
` 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 REMSTM program (formerly known as the “RevAssist® program”) [see Warnings and
`Precautions (5.2)].
`
`
`Reference ID: 3319577
`
`

`

`
`
`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 women with
`regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].
`
`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 28 days after discontinuing REVLIMID, even if they
`have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)].
`
`Blood Donation
`Patients must not donate blood during treatment with REVLIMID and for 1 month 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 REMSTM 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 REMSTM program (formerly known as the “RevAssist®” 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-Prescriber 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 (8.6)]
`and males must comply with contraception requirements [see Use in Specific Populations (8.6)].
` 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.
`
`5.3 Hematologic Toxicity
`REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood
`counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete
`blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their
`complete blood counts monitored 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 [see Dosage and Administration (2.1, 2.2, 2.3)].
`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)].
`In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and
`dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].
`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.
`
`5.4 Venous Thromboembolism
`Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple
`myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide
`monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID
`and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy
`prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures
`should be done carefully after an assessment of an individual patient’s underlying risk factors.
`5.5 Allergic Reactions
`Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been
`reported. 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 or TEN is suspected and should not be resumed following discontinuation for
`these reactions.
`
`Reference ID: 3319577
`
`

`

`
`
`REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.
`5.6 Tumor Lysis Syndrome
`Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are
`those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
`5.7 Tumor Flare Reaction
`Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node
`swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged.
`Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. 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. Lenalidomide 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 lenalidomide 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.
`5.8 Hepatotoxicity
`
`Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials,
`15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma
`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 Second Primary Malignancies
`
`Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of
`second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms
`who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account
`both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.
`
`
`
`ADVERSE REACTIONS
`
` 6
`
`
`The following adverse reactions are described in detail in other labeling sections:
`
`o Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)]
`o Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)]
`o Allergic Reactions [see Warnings and Precautions (5.5)]
`o
`Tumor lysis syndrome [see Warnings and Precautions (5.6)]
`o
`Tumor flare reactions [see Warnings and Precautions (5.7)]
`o Hepatotoxicity [see Warnings and Precautions (5.8)]
`o
`Second Primary Malignancies [see Warnings and Precautions (5.9)]
`
`
`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.
`
`6.1 Clinical Trials Experie