`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Pregnancy (Boxed Warnings, 4.1, 5.1, 8.1).
`
`Demonstrated hypersensitivity to lenalidomide (4.2, 5.5).
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`
`
`
`
`-----------------------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).
`
`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)
`
`
`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)
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`
`
`
`
`
`
`
`
`
`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 (2.1, 2.2).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 02/2013
`
`
`
`
`
`
`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
`Contraindications (4)
`02/13
`
`Warnings and Precautions (5.1, 5.2, 5.9)
`02/13
`
`
`
`---------------------------INDICATIONS AND USAGE----------------------------
`
`REVLIMID is a thalidomide analogue indicated for the treatment of:
`
` Multiple myeloma (MM), in combination with dexamethasone, in
`
`patients who have received at least one prior therapy (1.1).
`Patients with 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).
`
`
`
`
`
`
`
`
`
`
`-----------------------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).
`
`
`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) (2.1, 2.2).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3258475
`
`
`
`
`
`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
`
`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
`
`3
`4
`
`6
`
`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
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`2.1 Multiple Myeloma
`
`2.2 Myelodysplastic Syndromes
`
`DOSAGE FORMS AND STRENGTHS
`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
`
`
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience in Multiple Myeloma
`
`6.2 Clinical Trials Experience in Myelodysplastic Syndromes
`
`6.3 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Digoxin
`
`
`7.2 Warfarin
`
`7.3 Concomitant Therapies That May Increase the Risk of Thrombosis
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`7
`
`8
`
`Reference ID: 3258475
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Recommended Course
`Interrupt REVLIMID treatment, follow CBC
`weekly
`Restart 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
`
`
`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
`
`
`
`1
`
`
`Multiple Myeloma
`1.1
`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.
`
`
`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.
`
`
`Multiple Myeloma
`2.1
`
`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 lenalidomide.
`
`Platelet counts
`
`Thrombocytopenia in MM
`
`
`INDICATIONS AND USAGE
`
`When Platelets
`Fall to <30,000/mcL
`
`Return to ≥30,000/mcL
`
`For each subsequent drop <30,000/mcL
`Return to ≥30,000/mcL
`
`
`Reference ID: 3258475
`
`
`
`
`
`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
`
`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 next lower dose level when toxicity has resolved
`to ≤ Grade 2.
`
`
`Starting Dose Adjustment for Renal Impairment in MM
`
`
`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 nonmalignant 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 multiple myeloma (MM) are as follows:
`
`
`
`
`
`Table 1: Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1 – 21 of each 28 day cycle)
`
`
`
`Category
`
`Moderate Renal
`
`Impairment
`
`
`Severe Renal
`
`Impairment
`
`End Stage Renal
`Disease
`
`
`Renal Function
`(Cockcroft-Gault)
`
`CLcr 30-60 mL/min
`
`CLcr < 30 mL/min (not
`requiring dialysis)
`
`CLcr < 30 mL/min (requiring
`
`dialysis)
`
`Dose
`
`10 mg
`Every 24 hours
`
`15 mg
`Every 48 hours
`
`5 mg
`
`Once daily. On dialysis days, administer
`the dose following dialysis.
`
`
`
`After initiation of REVLIMID therapy, subsequent REVLIMID dose modification should be based on individual patient treatment tolerance, as
`
`described elsewhere in this section.
`
`
`
`
`
`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
`
`Recommended Course
`When Platelets
`
`Interrupt REVLIMID treatment
`<30,000/mcL or <50,000/mcL
`
`Reference ID: 3258475
`
`
`
`
`
`with platelet transfusions
`
`Return to ≥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
`<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
`
`
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`
`Resume REVLIMID at 2.5 mg daily
`
`
`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
`
`
`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)
`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
`
`
`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 next lower dose level when toxicity has resolved
`to ≤ Grade 2.
`
`Starting Dose Adjustment for Renal Impairment in MDS:
`
`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 nonmalignant 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 myelodysplastic syndromes (MDS) are as follows:
`
`
`
`
`Reference ID: 3258475
`
`
`
`
`
`
`
`Table 2: Starting Dose Adjustment for Renal Impairment in Myelodysplastic Syndromes (Days 1 – 28 of each 28 day cycle)
`
`
`
`
`Category
`
`Moderate Renal
`
`Impairment
`Severe Renal
`
`Impairment
`
`
`End Stage Renal
`Disease
`
`
`Renal Function
`(Cockcroft-Gault)
`
`CLcr 30-60 mL/min
`
`CLcr < 30 mL/min (not
`requiring dialysis)
`
`
`CLcr < 30 mL/min
`(requiring dialysis)
`
`Dose
`
`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 should be based on individual patient treatment tolerance, as
`
`described elsewhere in this section.
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`REVLIMID 2.5 mg, 5 mg, 10 mg, 15 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
`
`25 mg: White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink
`
`
`4
`
`
`Pregnancy
`4.1
`
`
`
`
`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 non-human
`primates 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)].
`
`
`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
`
`
`CONTRAINDICATIONS
`
`
`
`Reference ID: 3258475
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`
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`
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`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.
`
`REVLIMID REMSTM program
`5.2
`
`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.
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`
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`
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`
`
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` 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.
`
`
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`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 may require dose interruption and/or dose
`
`reduction [see Dosage and Administration (2.1)].
`
`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 multiple myeloma studies 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)].
`
`
`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 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.
`REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.
`Tumor Lysis Syndrome
`5.6
`
`
`
`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.
`
` Tumor Flare Reaction
`5.7
`
`
`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 or lymphoma with lenalidomide outside of a well-monitored clinical trial is
`discouraged.
`
`
`Hepatotoxicity
`5.8
`
`
`
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`Reference ID: 3258475
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`5.9
`
`
`
` Second Primary Malignancies
`
`ADVERSE REACTIONS
`
`
`Cases of transient liver laboratory abnormalities (predominantly transaminases) were reported in patients treated with lenalidomide. Treatment
`
`with lenalidomide should be interrupted until the levels return to baseline. Successful re-challenge without recurrence of liver laboratory
`elevation was reported in some patients.
`
`
`
`
`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.
`
`
`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)]
`
`
`
`
`Clinical Trials Experience in Multiple Myeloma
`
`
`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
`
`Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or
`
`placebo/dexamethasone (350 patients).
`
`
`In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction
`of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption
`with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption
`with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse
`events were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.
`
`
`Tables 3, 4, and 5 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.
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`
`
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`Table 3: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the
`
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`REVLIMID/dexamethasone and Placebo/dexamethasone Groups
`
`
`System Organ Class/ Preferred Term
`
`
`Blood and lymphatic system disorders
`Neutropenia %
`
`Anemia @
`
`Thrombocytopenia @
`
`Leukopenia
`Lymphopenia
` General disorders and administration site conditions
`Fatigue
`Pyrexia
`Peripheral edema
`Chest Pain
`
`Lethargy
`Gastrointestinal disorders
`Constipation
`Diarrhea@
`
`Nausea @
`
`
`Reference ID: 3258475
`
`
`REVLIMID/Dex*
`
`(n=353)
`n (%)
`
`Placebo/Dex *
`
`(n=350)
`n (%)
`
`
` 149 (42.2)
`
` 111 (31.4)
` 76 (21.5)
`
`28 (7.9)
`19 (5.4)
`
`
`155 (43.9)
`
`97 (27.5)
`
`93 (26.3)
`
`29 ( 8.2)
`
`24 ( 6.8)
`
`
`143 (40.5)
`
` 136 (38.5)
` 92 (26.1)
`
`
`
` 22 (6.3)
`
` 83 (23.7)
`
` 37 (10.6)
`4 (1.1)
`5 (1.4)
`
`
`146 (41.7)
`
`82 (23.4)
`
`74 (21.1)
`
`20 (5.7)
`
`8 (2.3)
`
`
`74 (21.1)
`
` 96 (27.4)
`
` 75 (21.4)
`
`
`
`
`
`
`REVLIMID/Dex*
`
`(n=353)
`n (%)
` 43 (12.2)
`
`35 (9.9)
`25 (7.1)
`
`Placebo/Dex *
`
`(n=350)
`n (%)
`
` 33 (9.4)
`22 (6.3)
`13 (3.7)
`
`
`118 (33.4)
`
`91 (25.8)
`
`48 (13.6)
`
`42 (11.9)
`
`
`82 (23.2)
`
`75 (21.2)
`
`54 (15.3)
`
`36 (10.2)
`23 (6.5)
`
`
`83 (23.5)
`62 (17.6)
`
`48 (13.6)
`
`40 (11.3)
`
`87 (24.6)
`
`
` 48 (13.6)
`30 (8.5)
`26 (7.4)
`
`
` 75 (21.2)
`35 (9.9)
`
`33 (9.3)
`27 (7.6)
`
`55 (15.6)
`
`48 (13.6)
`
`31 (8.8)
`24 (6.8)
`23 (6.5)
`24 (6.8)
`
`
`69 (19.5)
`
`
`61 (17.3)
`
`
`33 (9.3)
`28 (7.9)
`25 (7.1)
`
`
`74 (21.1)
`
`65 (18.6)
`
`39 (11.