`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 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 (5.2).
`
`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 AND ARTERIAL THROMBOEMBOLISM
`
`
`
`
`
`
` Significantly increased risk of deep vein thrombosis (DVT) and
`•
` pulmonary embolism (PE), as well as risk of myocardial infarction
`
`
`
`
`
`
`
` and stroke in patients with multiple myeloma receiving REVLIMID
`
` with dexamethasone. Anti-thrombotic prophylaxis is recommended
`
`
` (5.4).
`
`
`
`
`•
`
`
`--------------------------RECENT MAJOR CHANGES---------------------------­
`
`
`
`
`
`
`
`
`
`Boxed Warning
`09/14
`
`
`
`
`
`
`
`
`Indication and Usage (1.4)
`11/13
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.4)
`09/14
`
`
`
`
`
`
`
`Warnings and Precautions (5.5, 5.10)
`11/13
`
`
`
`---------------------------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).
`
`Limitations of Use:
`
`
`
`
`
`
`
`REVLIMID is not indicated and is not recommended for the treatment
`•
`
`of patients with chronic lymphocytic leukemia (CLL) outside of
`
`controlled clinical trials (1.4).
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`• MM: 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).
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`
`
`
`
`Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg (3).
`•
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`Reference ID: 3627118
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`Pregnancy (Boxed Warning, 4.1, 5.1, 8.1).
`
`
`
`•
`
`
`
`
`Demonstrated hypersensitivity to lenalidomide (4.2, 5.5).
`•
`
`
`-----------------------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 multiple myeloma receiving
`
`REVLIMID (5.6).
`
`
`Hepatotoxicity: Hepatic failure including fatalities; monitor liver
`
`
`
`
`function. Stop REVLIMID and evaluate if hepatotoxicity is suspected
`
`(5.7).
`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 (5.8).
`
`
`
`
`Tumor lysis syndrome (TLS) including fatalities: Monitor patients at
`
`
`
`
`
`risk of TLS (i.e., those with high tumor burden) and take appropriate
`
`precautions (5.9).
`
`
`
`Tumor flare reaction: Serious tumor flare reactions have occurred
`
`
`
`
`during investigational use of REVLIMID for chronic lymphocytic
`
`
`
`leukemia and lymphoma (5.10, 6.3).
`
`-------------------------------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 contact Celgene
`
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-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
`
`
`thrombosis (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 (2.4).
`
`
`•
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`
`Revised: 09/2014
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`3
`
`4
`
`
`FULL PRESCRIBING INFORMATION CONTENTS*
`
`
`WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC
`
`
`
`
`TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`1.1 Multiple Myeloma
`
`
`
`
`1.2 Myelodysplastic Syndromes
`
`
`
`
`
`1.3 Mantle Cell Lymphoma
`
`
`
`
`1.4 Limitations of Use
`
`
`
`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
`
`
`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 and Arterial Thromboembolism
`
`
`
`5.5
`Increased Mortality in Patients with CLL
`
`
`
`5.6 Second Primary Malignancies
`
`
`
`5.7 Hepatotoxicity
`
`
`
`5.8 Allergic Reactions
`
`
`
`
`5.9 Tumor Lysis Syndrome
`
`
`
`5.10 Tumor Flare Reaction
`
`
`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
`
`
`DRUG INTERACTIONS
`
`
`7.1 Digoxin
`
`
`
`7.2 Warfarin
`
`
`
`
`
`
`6
`
`
`7
`
`
`
`8
`
`
`7.3 Concomitant Therapies That May Increase the Risk of Thrombosis
`
`
`
`
`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
`
`Reference ID: 3627118
`
`

`

`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
` WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM
`
` Embryo-Fetal Toxicity
`
`Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental
`
`
`
`monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used
`
`
`
`
`during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy
`
`
`
`
`
`
`
`
`
`
`tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously
`
`
`
`
`
`
`abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication
`
`
`
`
`
`
`
`Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program,
`
`
`
`
`
`
`
`the REVLIMID 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 and Arterial Thromboembolism
`REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as
`
`
`
`risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone
`
`
`
`
`
`therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical
`
`
`
`
`
`
`care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and
`
`
`
`the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].
`
`
`
`
`
`
`
`
`
`
`1
`
`
`
`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.
`
`
`Myelodysplastic Syndromes
`1.2
`
`
`
`
`
`
`
`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.
`
`
`
`Mantle Cell Lymphoma
`1.3
`
`
`
`
`
`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.
`
`
`Limitations of Use:
`1.4
`
`
`
`
`
`
`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)].
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`Reference ID: 3627118
`
`

`

`
`
`Platelet counts
`
`
`Thrombocytopenia in MM
`
`
`
` When Platelets
`
` Fall to <30,000/mcL
`
`
`
` Return to ≥30,000/mcL
`
`
` 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
`
`
`
` 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
`
`
`
`
`
`
`
`
` 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.
`
`
`Myelodysplastic Syndromes
`2.2
`
`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
`
`
`
`
`
`
`Reference ID: 3627118
`
`
` 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
`
`
`
` Resume REVLIMID at 5 mg daily
`
`
`
`
`
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`
`
`
`
`If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS
`
`
` Recommended Course
` When Platelets
` <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
`
`

`

`
`
`
`
`
`
` Resume REVLIMID at 2.5 mg daily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`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
`
`
`
`
`
` Resume REVLIMID at 2.5 mg daily
`
`
`
`
` When Neutrophils
`
` <500/mcL for ≥7 days or <500/mcL
`
`
` associated with fever (≥38.5°C)
`
`
`
`
` Return to ≥500/mcL
`
`
`
`
` 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.
`
`
`Mantle Cell Lymphoma
`2.3
`
`
`
`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
`
`Reference ID: 3627118
`
`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
`
`

`

`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.
`
`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
`
`
`
`Interrupt REVLIMID treatment and follow
`CBC weekly
`
`
`Resume REVLIMID at 5 mg less than the
`previous dose. Do not dose below 5 mg daily
`
`
`
`Starting Dose for Renal Impairment in MM, MDS or MCL
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`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
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described
`
`
`elsewhere (see section 2).
`
`
`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
`
`
`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)].
`
`
`
`
`
`
`Allergic Reactions
`4.2
`
`
`
`
`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)].
`
`
`
`
`Reference ID: 3627118
`
`

`

`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`5
`
`
`Embryo-Fetal Toxicity
`5.1
`
`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)].
`
`
`
`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
`
`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-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 (8.6)]
`
`
`
`
`
`
`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.
`
`
`
`
`REVLIMID REMSTM program
`
`
`
`
`Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at
`
`
`
`
`
`1-888-423-5436.
`
`
`
`Hematologic Toxicity
`5.3
`
`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.
`
`
`
`Venous and Arterial Thromboembolism
`5.4
`
`
`
`
`
`
`
`
`Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with
`
`
`
`
`
`
`
`
`
`
`
`REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma who were treated with
`
`Reference ID: 3627118
`
`

`

`
`
`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 [see Boxed Warning and Adverse Reactions (6.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma who were treated with REVLIMID and
`dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials [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 multiple myeloma 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
`
`
`
`
`
`
`
`
`
`2.7 months. 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 the