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: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP
`
`
`VEIN THOMBOSIS AND PULMONARY EMBOLISM
`
`See full prescribing information for complete boxed warning.
`Fetal Risk
`
`
`x
`
`x
`
`x
`
`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 death to a developing baby.
`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 under a restricted distribution
`program called “RevAssist.” (5.2, 17).
`
`
`Hematologic Toxicity
`REVLIMID can cause significant neutropenia and
`x
`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).
`
`Deep Vein Thrombosis and Pulmonary Embolism
`Significantly increased risk of DVT and PE in patients with multiple
`x
`myeloma receiving REVLIMID with dexamethasone (5.4).
`
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`
`
`Dosage and Administration (2, 2.1, 2.2)
`12/11
`
`
`
`
`Dosage Forms and Strengths (3)
`12/11
`
`
`
`Warnings and Precautions (5.2, 5.5, 5.8)
`03/12
`
`Adverse Reactions – Postmarketing Experience (6.3)
`12/11
`
`
`
`
`Drug Interactions (7, 7.1, 7.2)
`12/11
`
`
`
`
`12/11
`Use in Special Populations (8.6)
`
`
`
`
`
`
` 12/11
`Overdosage (10)
`
`
`
`
`
`
` 12/11
`Description (11)
`
`
`
`
`
` 12/11
`Clinical Pharmacology (12.3)
`
`
`How Supplied/Storage and Handling (16)
`12/11
`
`
`
`Patient Counseling Information (17)
`12/11
`
`---------------------------INDICATIONS AND USAGE----------------------------
`
`REVLIMID is a thalidomide analogue indicated for the treatment of:
`
`x 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).
`
`x
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
`x 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).
`
`x MDS: 10 mg once daily (2.2).
`Continue or modify dosing based on clinical and laboratory findings
`x
`
`(2.1, 2.2).
`Renal impairment: Adjust starting dose in patients with moderate or
`
`severe renal impairment (CLcr<60 mL/min) (2.1, 2.2).
`
`x
`
`
`
`Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg and 25 mg (3).
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`x
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`
`
`Reference ID: 3128570
`
`
`
`Pregnancy (Boxed Warnings, 4.1, 5.1, 8.1).
`Demonstrated hypersensitivity to lenalidomide (4.2, 5.5).
`
`x
`x
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`Females of childbearing potential: Must have 2 negative pregnancy tests
`before starting treatment with REVLIMID and must use two forms of
`contraception or continuously abstain from heterosexual sex during and
`for 4 weeks after treatment. Reproductive Risk and Special Prescribing
`Requirements: To avoid fetal exposure REVLIMID is only available
`under a special restricted distribution program called RevAssist (Boxed
`
`Warnings, 4.1, 5.1, 17).
`Hematologic Toxicity: This drug is associated with significant
`
`neutropenia and thrombocytopenia. Patients may require dose
`interruption and/or dose reduction (5.3, 6.1).
`Deep vein thrombosis and pulmonary embolism: Physicians and patients
`should be observant for signs and symptoms of thromboembolism (5.4,
`
`6.1).
`Allergic Reactions: include hypersensitivity, angioedema, Stevens-
`Johnson syndrome, and toxic epidermal necrolysis. In some cases these
`allergic reactions may be fatal. Discontinue REVLIMID if any such
`reactions are suspected. Revlimid 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 (5.5).
`Tumor lysis syndrome (TLS): Fatal instances of TLS have been
`reported during treatment with lenalidomide. 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------------------------------
`
`x 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)
`x 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, contact Celgene
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
`
`x
`
`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 thromboembolic events (VTE) .(7.3)
`
`
`x
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`x
`
`Patients with Renal Insufficiency: Adjustment of the starting dose of
`REVLIMID is recommended in patients with moderate or severe renal
`
`impairment and in patients on dialysis (2.1, 2.2).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 03/2012
`
`
`
`
`

`

`13.
`
`8.1. Pregnancy
`
`8.3. Nursing mothers
`
`8.4. Pediatric use
`
`8.5. Geriatric use
`8.6. Renal Impairment
`
`8.7. Hepatic Impairment
`
`10. OVERDOSAGE
` DESCRIPTION
`11.
`12.
` CLINICAL PHARMACOLOGY
`12.1. Mechanism of action
`
`
`12.3. Pharmacokinetics
`
` NONCLINICAL TOXICOLOGY
`13.1. Carcinogenesis, mutagenesis, impairment of fertility
`
`13.3 Reproductive and Developmental Toxicity
`
`
` CLINICAL STUDIES
`
`14.1 Multiple Myeloma
`
`
`14.2 Myelodysplastic Syndromes (MDS) with a Deletion 5q
`
`
`
` Cytogenetic Abnormality
`
` REFERENCES
`15.
`16. HOW SUPPLIED/STORAGE AND HANDLING
`17. PATIENT COUNSELING INFORMATION
`
`17.1 Importance of Preventing Pregnancy
`
`17.2 Hematologic Toxicity
`
`
`
`17.3 Deep Vein Thrombosis and Pulmonary Embolism
`
`17.4 Dosing Instructions
`
`
`
`14.
`
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`listed
`
`
`
`FULL PRESCRIBING INFORMATION CONTENTS*
`WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP
`
`VEIN THROMBOSIS AND PULMONARY EMBOLISM
`1.
` INDICATIONS AND USAGE
`1.1 Multiple Myeloma
`
`
`1.2 Myelodysplastic Syndromes
`
`
`2.
` DOSAGE AND ADMINISTRATION
`
`2.1 Multiple Myeloma
`
`
`2.2 Myelodysplastic Syndromes
`
`3. DOSAGE FORMS AND STRENGTHS
`4.
` CONTRAINDICATIONS
`4.1 Pregnancy
`
`4.2 Allergic Reactions
`
`5. WARNINGS AND PRECAUTIONS
`5.1 Fetal Risk
`
`
`5.2 Reproductive Risk and Special Prescribing Requirements
`
`(RevAssist Program)
`
`5.3 Hematologic Toxicity
`
`5.4 Deep Vein Thrombosis and Pulmonary Embolism
`
`
`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
`
`8. USE IN SPECIFIC POPULATIONS
`
`7.
`
`6.
`
`Reference ID: 3128570
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`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: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
`
`
`
`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 death to a developing baby. In women of childbearing potential, obtain 2 negative
`pregnancy tests before starting REVLIMID® treatment. Women of childbearing 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 fetal exposure to lenalidomide, REVLIMID is only available under a restricted distribution program
`
`called “RevAssist®” (5.2).
`
`
`Information about the RevAssist program is available at www.REVLIMID.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)].
`
`
`Deep Vein Thrombosis and Pulmonary Embolism 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 thromboembolic events. 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.
`
`REVLIMIDin 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
`REVLIMIDis 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
`
`REVLIMIDshould 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 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
`
`Absolute Neutrophil counts (ANC)
`
`Neutropenia in MM
`
`Reference ID: 3128570
`
`

`

`
`
`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 REVLIMD 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
`with platelet transfusions
`
`Return to •30,000/mcL
`
`(without hemostatic failure)
`
`
`Resume REVLIMID at 5 mg daily
`
`Reference ID: 3128570
`
`

`

`
`
`
`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
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`Recommended Course
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg daily
`
`
`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
`
`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 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: 3128570
`
`

`

`
`
`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.
`
`CONTRAINDICATIONS
`
`
`
`After initiation of REVLIMID therapy, subsequent REVLIMID dose modification should be based on individual patient treatment tolerance, as
`described elsewhere in this section.
`3.
`DOSAGE FORMS AND STRENGTHS
`
`
`REVLIMID 2.5 mg, 5 mg, 10 mg, 15 mg and 25 mg capsules will be supplied through the RevAssist 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 may cause fetal harm when administered to a pregnant woman. 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 pregnant women and
`women capable of becoming pregnant [see Boxed Warning]. Females of childbearing potential may be treated with lenalidomide provided
`
`
`
`adequate precautions are taken to avoid pregnancy. Females must commit either to abstain continuously from heterosexual sexual intercourse or
`to use two methods of reliable birth control, including at least one highly effective method (e.g., hormonal contraception, tubal ligation, IUD or
`partner’s vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating
`
`treatment with REVLIMID, during therapy, during dose interruptions , and continuing for 4 weeks following discontinuation of REVLIMID
`
`
`therapy. If hormonal or IUD contraception is medically contraindicated, two other effective or highly effective methods may be used.
`
`Females of childbearing potential being treated with REVLIMID must have pregnancy testing (sensitivity of at least 50 mIU/mL). The first test
`should be performed within 10-14 days and the second test within 24 hours prior to beginning 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.
`
`Pregnancy testing and counseling must be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If
`
`
`pregnancy occurs, REVLIMID must be immediately discontinued. Under these conditions, the patient should be referred to an
`obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
`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
`Fetal Risk
`
`REVLIMID is a thalidomide analogue. Thalidomide is a known human teratogen that causes life-threatening human birth defects. An
`
`embryofetal 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. If
`
`REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby. Females of childbearing potential must be
`advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used during therapy, during dose interruptions
`and for at least 4 weeks after completing therapy.
`
`There are no adequate and well-controlled studies in pregnant females.
`
`Reproductive Risk and Special Prescribing Requirements (RevAssist Program)
`5.2
`
`
`
`Reference ID: 3128570
`
`

`

`
`
`Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available under a special restricted distribution program called
`
`"RevAssist". Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and
`meet all the conditions of the RevAssist program.
`
`Please see the following information for prescribers, female patients, and male patients about this restricted distribution program.
`
`RevAssist Program Description
`Prescribers
`REVLIMID can be prescribed only by licensed prescribers who are registered in the RevAssist program and understand the potential risk of
`
`teratogenicity if lenalidomide is used during pregnancy.
`
`Effective contraception must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID therapy,
`during therapy, during dose interruptions and for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated
`
`even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least
`24 consecutive months. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually
`mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal naturally
`for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females
`of childbearing potential. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual
`sexual contact is the chosen method.
`Females of childbearing potential must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The first test should be performed
`within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. A prescription for REVLIMID for a female of
`childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.
`Male Patients: Clinical data has demonstrated the presence of lenalidomide in human semen. Male patients taking REVLIMID should not donate
`
`sperm.
`Males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential even if they have
`undergone a successful vasectomy.
`Once treatment has started and during dose interruptions, pregnancy testing for females of childbearing potential should occur weekly
`
`
`during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual
`
`cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses
`her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding. REVLIMID treatment must be discontinued during
`this evaluation.
`Pregnancy test results should be verified by the prescriber and the pharmacist prior to dispensing any prescription.
`If pregnancy does occur during treatment, REVLIMID must be discontinued immediately.
`Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch number at 1-800-332-1088 and also to Celgene
`Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further
`
`evaluation and counseling.
`Female Patients
`REVLIMID may be used in females of childbearing potential only when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS
`
`(i.e., she is unable to become pregnant while on REVLIMID therapy):
`
`x
`
`x
`
`x
`
`x
`
`she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as
`
`
`described in the RevAssist program.
`
`
`she has received and understands both oral and written warnings of the potential risks of taking REVLIMID during pregnancy and of
`exposing a fetus to the drug.
`
`she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of
`
`contraception simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections,
`
`patch or implants) or partner’s vasectomy and one additional effective contraceptive method - latex condom, diaphragm or cervical cap,
`
`unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature females who have not undergone a
`
`
`hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the
`preceding 24 consecutive months), or had a bilateral oophorectomy are considered to be females of childbearing potential.
`she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4
`weeks prior to beginning REVLIMID therapy, during therapy, during dose interruptions and for 4 weeks after discontinuation of therapy.
`
`x
`
`x
`
`she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL, within 10-14 days and 24 hours prior to beginning
`therapy.
`
`if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed to ensure
`
`compliance with the above.
`Male Patients
`
`
`
`
`
`REVLIMID may be used in sexually active males when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:
`
`Reference ID: 3128570
`
`

`

`
`
`x
`
`x
`x
`
`x
`
`he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey
`as described in the RevAssist program.
`
`he has received and understands both oral and written warnings of the potential risks of taking REVLIMID and exposing a fetus to the drug.
`
`he has received both oral and written warnings of the risk of possible contraception failure and that it is known that lenalidomide is present
`in semen. He has been instructed that he must always use a latex condom during any sexual contact with females of childbearing potential,
`
`
`even if he has undergone a successful vasectomy. Females of childbearing potential are considered to be sexually mature females who have
`
`not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal for at least 24 consecutive
`
`
`months (i.e., who have had menses at any time in the preceding 24 consecutive months).
`
`he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with
`females of childbearing potential, even if he has undergone a successful vasectomy.
`
`
`x
`
`
`if the patient is between 12 and 18 years of age, his parent or legal guardian must have read the educational materials and agreed to ensure
`
`compliance with the above.
`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 Warnin