`2
`3
`4
`5
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`
`6
`7
`8
`9
`10
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`43
`44
`45
`46
`47
`
`48
`
`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
`
`Initial U.S. Approval: 2005
`
`
`
`WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP
`
`
`VEIN THOMBOSIS AND PULMONARY EMBOLISM
`
`See full prescribing information for complete boxed warning.
`
`Fetal Risk
`
`
`
`•
`
`
`•
`
`
`•
`
`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
`
`•
`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
`
`•
`myeloma receiving REVLIMID with dexamethasone (5.4).
`
`
`
`-----------------------------RECENT MAJOR CHANGES------------------------
`
`
` 03/10
`Boxed Warning
`
`
`Indications and Usage (1.1, 1.2)
` 03/10
`
`
`
`Dosage and Administration (2.1, 2.2)
`03/10
`
`Contraindications (4.1, 4.2)
`03/10
`
`
`
`
`Warnings and Precautions (5)
`03/10
`
`
`Patients with Renal Impairment (8.6)
`03/10
`
`------------------------------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 (CLcr<60 mL/min) (2.1, 2.2).
`
`•
`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`
`
`
`
` Capsules: 5 mg, 10 mg, 15 mg and 25 mg (3).
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`Pregnancy (Boxed Warnings, 4.1, 5.1, 8.1).
`
`
`•
`
`Demonstrated hypersensitivity to lenalidomide (4.2, 5.5).
`
`•
`--------------------------WARNINGS AND PRECAUTIONS---------------------
`
`
`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 (5.5). REVLIMID should not be resumed following discontinuation for these reactions.
`
`
`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).
`
`--------------------------------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; contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
` 1
`
`
`
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`
`
` Digoxin: Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax 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)
`
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`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: ____
`
`
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`
`
`60
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`61 WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
`
`
`
`62
`
`INDICATIONS AND USAGE
`
`1
`63
`
`
`1.1 Multiple Myeloma
`64
`
`1.2 Myelodysplastic Syndromes
`
`65
`
`2 DOSAGE AND ADMINISTRATION
`
`
`66
`
`2.1 Multiple Myeloma
`
`67
`
`2.2 Myelodysplastic Syndromes
`
`68
`
`3 DOSAGE FORMS AND STRENGTHS
`
`69
`
`4 CONTRAINDICATIONS
`
`70
`
`
`4.1 Pregnancy
`71
`
`4.2 Allergic Reactions
`
`72
`
`5 WARNINGS AND PRECAUTIONS
`
`73
`
`5.1
` Fetal Risk
`74
`
`5.2 Reproductive Risk and Special Prescribing Requirements
`75
`
`
`5.3 Hematologic Toxicity
`76
`
`
`
`5.4 Deep Vein Thrombosis and Pulmonary Embolism
`77
`
`5.5 Allergic Conditions
`78
`
`
`5.6 Tumor Lysis Syndrome
`79
`
`5.7 Tumor Flare Reaction
`
`80
`
`6 ADVERSE REACTIONS
`
`81
`
`6.1 Clinical Trials Experience in Multiple Myeloma
`82
`
`6.2 Clinical Trials Experience in Myelodysplastic Syndromes
`83
`
`6.3 Postmarketing Experience
`
`84
`
`7 DRUG INTERACTIONS
`
`85
`
`7.1
` Digoxin
`
`86
`
`7.2 Warfarin
`87
`
`7.3 Drugs that Increase the Risk of Thrombosis
`
`88
`
`8 USE IN SPECIFIC POPULATIONS
`
`89
`
`
`8.1 Pregnancy
`90
`
`8.3 Nursing Mothers
`91
`
`8.4 Pediatric Use
`92
`
`8.5 Geriatric Use
`93
`
`8.6 Renal Impairment
`94
`
`8.7 Hepatic Impairment
`95
`
`10 OVERDOSAGE
`96
`11 DESCRIPTION
`97
`12 CLINICAL PHARMACOLOGY
`98
`
`12.1 Mechanism of Action
`99
`
`12.3 Pharmacokinetics
`
`
`100
`13 NONCLINICAL TOXICOLOGY
`101
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`102
`
` 13.3 Reproductive and Developmental Toxicity
`
`
`103
`14 CLINICAL STUDIES
`104
`14.1 Multiple Myeloma
`
`105
`14.2 Myelodysplastic Syndromes
`106
`15 REFERENCES
`107
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`108
`17 PATIENT COUNSELING INFORMATION
`109
`Importance of Preventing Pregnancy
` 17.1
`
`
`110
`17.2 Hematologic Toxicity
`
`111
`17.3 Deep Vein Thrombosis and Pulmonary Embolism
`
`
`
`112
`
`
`17.4 Medication Guide
`113
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`114
`FULL PRESCRIBING INFORMATION
`
`115 WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
`
`
`116
`Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental
`117
`monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used
`118
`during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative
`119
`pregnancy tests before starting REVLIMID® treatment. Women of childbearing potential must use 2 forms of contraception or
`
`
`
` 2
`
`
`
`
`
`
`120
`121
`122
`123
`124
`125
`126
`127
`128
`129
`130
`131
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`
`165
`166
`167
`168
`
`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.
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`1.1 Multiple Myeloma
`REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have
`received at least one prior therapy.
`
`1.2 Myelodysplastic Syndromes
`REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk
`myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic
`abnormalities.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`2.1 Multiple Myeloma
`The recommended starting dose of REVLIMID is 25 mg once daily orally with water on Days 1-21 of repeated 28-day cycles. Patients
`should not break, chew or open the capsules. 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
`
`
`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
`
`
`
`3
`
`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
`
`
`
`
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`
`185
`186
`187
`188
`189
`190
`191
`192
`193
`194
`195
`196
`
`197
`198
`
`199
`200
`201
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.2 Myelodysplastic Syndromes
`The recommended starting dose of REVLIMID is 10 mg daily with water. Patients should not break, chew or open the capsules.
`
`
`
`
`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
`
`
` 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 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
`
`
`
`
`For each subsequent drop <1,000/mcL
`
`Return to ≥1,000/mcL
`
`Interrupt REVLIMID treatment
`Resume REVLIMID at 5 mg less than the
`
`previous dose. Do not dose below 5 mg daily
`
`
`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.
`
`
`
`
`
`
`
` 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)
`
`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 5 mg daily
`
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`
`
`4
`
`
`
`202
`203
`204
`205
`
`206
`207
`208
`
`209
`210
`211
`
`212
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`
`
`
`
`Resume REVLIMID at 5 mg every other day
`
` 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
`
`
`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
`
`
`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
`
`
`Recommended Course
`Interrupt REVLIMID treatment
`
`
`Resume REVLIMID at 5 mg every other day
`
`
`
` 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:
`
`
`
`
`
`
`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
`5 mg
`
`Every 48 hours
`
`5 mg
`
`3 times a week following each dialysis
`
`
`
`After initiation of REVLIMID therapy, subsequent REVLIMID dose modification should be based on individual patient treatment
`tolerance, as described elsewhere in this section.
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`3 DOSAGE FORMS AND STRENGTHS
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` REVLIMID 5 mg, 10 mg, 15 mg and 25 mg capsules will be supplied through the RevAssist program
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`REVLIMID is available in the following capsule strengths:
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`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
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`25 mg: White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink
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`4 CONTRAINDICATIONS
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`4.1 Pregnancy
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` REVLIMID may cause fetal harm when administered to a pregnant woman. Limb abnormalities were seen in the offspring of
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`monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this
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`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
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`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
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`therapy, during therapy delay, 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.
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`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
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`weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with
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`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
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`patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
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` Allergic Reactions
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`REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome,
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`toxic epidermal necrolysis) to lenalidomide [see Warnings and precautions (5.5)}.
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`5 WARNINGS AND PRECAUTIONS
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`4.2.
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`5.1 Fetal Risk
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`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
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`childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used
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`during therapy, during therapy interruptions and for at least 4 weeks after completing therapy.
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`There are no adequate and well-controlled studies in pregnant females.
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` Reproductive Risk and Special Prescribing Requirements (RevAssist Program)
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`Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available under a special restricted distribution
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`program called "RevAssist". Prescribers and pharmacists registered with the program can prescribe and dispense the product to
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`patients who are registered and meet all the conditions of the RevAssist program.
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`Please see the following information for prescribers, female patients, and male patients about this restricted distribution program.
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`RevAssist Program Description
`Prescribers
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`REVLIMID can be prescribed only by licensed prescribers who are registered in the RevAssist program and understand the potential
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`risk of teratogenicity if lenalidomide is used during pregnancy.
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`Effective contraception must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID
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`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
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`provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy, have not had a
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`bilateral oophorectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses
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`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
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`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
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`prescriber.
`Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving
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`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
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`weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual
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`cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should
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`be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding.
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`REVLIMID treatment must be discontinued during this evaluation.
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`Pregnancy test results should be verified by the prescriber and the pharmacist prior to dispensing any prescription.
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`5.2
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` If pregnancy does occur during treatment, REVLIMID must be discontinued immediately.
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`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
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`toxicity for further evaluation and counseling.
`Female Patients
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`REVLIMID may be used in females of childbearing potential only when the PATIENT MEETS ALL OF THE FOLLOWING
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`CONDITIONS (i.e., she is unable to become pregnant while on REVLIMID therapy):
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`she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient
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`survey as described in the RevAssist program.
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`she has received and understands both oral and written warnings of the potential risks of taking REVLIMID during pregnancy
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`and of exposing a fetus to the drug.
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`she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable
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`forms of contraception simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control
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`pills, injections, patch or implants) or partner’s vasectomy and one additional effective contraceptive method - latex condom,
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`diaphragm or cervical cap, unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature
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`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
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`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
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`after discontinuation of therapy.
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`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
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`beginning therapy.
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`if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed
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`to ensure compliance with the above.
`Male Patients
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`REVLIMID may be used in sexually active males when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:
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` he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and
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`patient survey as described in the RevAssist program.
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`he has received and understands both oral and written warnings of the potential risks of taking REVLIMID and exposing a fetus
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`he has received both oral and written warnings of the risk of possible contraception failure and that it is unknown whether
` lenalidomide is present in semen. He has been instructed that he must always use a latex condom during any sexual contact with
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`females of childbearing potential, even if he has undergone a successful vasectomy. Females of childbearing potential are
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`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
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`24 consecutive months).
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`he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual
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`contact with females of childbearing potential, even if he has undergone a successful vasectomy.
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` if the patient is between 12 and 18 years of age, his parent or legal guardian must have read the educational materials and agreed
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`to ensure compliance with the above.
`5.3 Hematologic Toxicity
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`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