Revlimid Drug Information

• The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: o Embryo-Fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.1 , 5.2) ] o Hematologic Toxicity [see Boxed Warning , Warnings and Precautions (5.3) ] o Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.4) ] o Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5) ] o Second Primary Malignancies [see Warnings and Precautions (5.6) ] o Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7) ] o Hepatotoxicity [see Warnings and Precautions (5.8) ] o Severe Cutaneous Reactions [see Warnings and Precautions (5.9) ] o Tumor Lysis Syndrome [see Warnings and Precautions (5.10) ] o Tumor Flare Reactions [see Warnings and Precautions (5.11) ] o Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12) ] o Thyroid Disorders [see Warnings and Precautions (5.13) ] o Early Mortality in Patients with MCL [see Warnings and Precautions (5.14) ] o Hypersensitivity [see Warnings and Precautions (5.15) ]
• MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor ( 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 ( 6.1 ).
• Non-Hodgkin's Lymphoma (NHL: MCL, FL or MZL): Most common adverse reactions (≥15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed MM – REVLIMID Combination Therapy: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms* Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable. f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse reactions included in combined adverse reaction terms : Abdominal Pain : Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias : Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis : Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash : Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis : Deep vein thrombosis, venous thrombosis limb, venous thrombosis Body System Adverse Reaction All Adverse Reactions a Grade 3/4 Adverse Reactions b Rd Continuous (N = 532) Rd18 (N = 540) MPT (N = 541) Rd Continuous (N = 532) Rd18 (N = 540) MPT (N = 541) General disorders and administration site conditions Fatigue % 173 (33) 177 (33) 154 (28) 39 ( 7) 46 ( 9) 31 ( 6) Asthenia 150 (28) 123 (23) 124 (23) 41 ( 8) 33 ( 6) 32 ( 6) Pyrexia c 114 (21) 102 (19) 76 (14) 13 ( 2) 7 ( 1) 7 ( 1) Non-cardiac chest pain f 29 ( 5) 31 ( 6) 18 ( 3) <1% < 1% < 1% Gastrointestinal disorders Diarrhea 242 (45) 208 (39) 89 (16) 21 ( 4) 18 ( 3) 8 ( 1) Abdominal pain % f 109 (20) 78 (14) 60 (11) 7 ( 1) 9 ( 2) < 1% Dyspepsia f 57 (11) 28 ( 5) 36 ( 7) <1% < 1% 0 ( 0) Musculoskeletal and connective tissue disorders Back pain c 170 (32) 145 (27) 116 (21) 37 ( 7) 34 ( 6) 28 ( 5) Muscle spasms f 109 (20) 102 (19) 61 (11) < 1% < 1% < 1% Arthralgia f 101 (19) 71 (13) 66 (12) 9 ( 2) 8 ( 1) 8 ( 1) Bone pain f 87 (16) 77 (14) 62 (11) 16 ( 3) 15 ( 3) 14 ( 3) Pain in extremity f 79 (15) 66 (12) 61 (11) 8 ( 2) 8 ( 1) 7 ( 1) Musculoskeletal pain f 67 (13) 59 (11) 36 ( 7) < 1% < 1% < 1% Musculoskeletal chest pain f 60 (11) 51 ( 9) 39 ( 7) 6 ( 1) < 1% < 1% Muscular weakness f 43 ( 8) 35 ( 6) 29 ( 5) < 1% 8 ( 1) < 1% Neck pain f 40 ( 8) 19 ( 4) 10 ( 2) < 1% < 1% < 1% Infections and infestations Bronchitis c 90 (17) 59 (11) 43 ( 8) 9 ( 2) 6 ( 1) < 1% Nasopharyngitis f 80 (15) 54 (10) 33 ( 6) 0 ( 0) 0 ( 0) 0 ( 0) Urinary tract infection f 76 (14) 63 (12) 41 ( 8) 8 ( 2) 8 ( 1) < 1% Upper respiratory tract infection c% f 69 (13) 53 ( 10) 31 ( 6) < 1% 8 ( 1) < 1% Pneumonia c@ 93 (17) 87 (16) 56 (10) 60 (11) 57 (11) 41 ( 8) Respiratory tract infection % 35 ( 7) 25 ( 5) 21 ( 4) 7 ( 1) < 1% < 1% Influenza f 33 ( 6) 23 ( 4) 15 ( 3) < 1% < 1% 0 ( 0) Gastroenteritis f 32 ( 6) 17 ( 3) 13 ( 2) 0 ( 0) < 1% < 1% Lower respiratory tract infection 29 ( 5) 14 ( 3) 16 ( 3) 10 ( 2) < 1% < 1% Rhinitis f 29 ( 5) 24 ( 4) 14 ( 3) 0 ( 0) 0 ( 0) 0 ( 0) Cellulitis c < 5% < 5% < 5% 8 ( 2) < 1% < 1% Sepsis c@ 33 ( 6) 26 ( 5) 18 ( 3) 26 ( 5) 20 ( 4) 13 ( 2) Nervous system disorders Headache f 75 (14) 52 ( 10) 56 (10) < 1% < 1% < 1% Dysgeusia f 39 ( 7) 45 ( 8) 22 ( 4) < 1% 0 ( 0.0) < 1% Blood and lymphatic system disorders d Anemia 233 (44) 193 (36) 229 (42) 97 (18) 85 (16) 102 (19) Neutropenia 186 (35) 178 (33) 328 (61) 148 (28) 143 (26) 243 (45) Thrombocytopenia 104 (20) 100 (19) 135 (25) 44 ( 8) 43 ( 8) 60 (11) Febrile neutropenia 7 ( 1) 17 ( 3) 15 ( 3) 6 ( 1) 16 ( 3) 14 ( 3) Pancytopenia < 1% 6 ( 1) 7 ( 1) < 1% < 1% < 1% Respiratory, thoracic and mediastinal disorders Cough f 121 (23) 94 (17) 68 (13) < 1% < 1% < 1% Dyspnea c,e 117 (22) 89 (16) 113 (21) 30 ( 6) 22 ( 4) 18 ( 3) Epistaxis f 32 ( 6) 31 ( 6) 17 ( 3) < 1% < 1% 0 ( 0) Oropharyngeal pain f 30 ( 6) 22 ( 4) 14 ( 3) 0 ( 0) 0 ( 0) 0 ( 0) Dyspnea exertional e 27 ( 5) 29 ( 5) < 5% 6 ( 1) < 1% 0 ( 0) Metabolism and nutrition disorders Decreased appetite 123 (23) 115 (21) 72 (13) 14 ( 3) 7 ( 1) < 1% Hypokalemia % 91 (17) 62 (11) 38 ( 7) 35 ( 7) 20 ( 4) 11 ( 2) Hyperglycemia 62 (12) 52 (10) 19 ( 4) 28 ( 5) 23 ( 4) 9 ( 2) Hypocalcemia 57 (11) 56 (10) 31 ( 6) 23 ( 4) 19 ( 4) 8 ( 1) Dehydration % 25 ( 5) 29 ( 5) 17 ( 3) 8 ( 2) 13 ( 2) 9 ( 2) Gout e < 5% < 5% < 5% 8 ( 2) 0 ( 0) 0 ( 0) Diabetes mellitus % e < 5% < 5% < 5% 8 ( 2) < 1% < 1% Hypophosphatemia e < 5% < 5% < 5% 7 ( 1) < 1% < 1% Hyponatremia % e < 5% < 5% < 5% 7 ( 1) 13 ( 2) 6 ( 1) Skin and subcutaneous tissue disorders Rash 139 (26) 151 (28) 105 (19) 39 ( 7) 38 ( 7) 33 ( 6) Pruritus f 47 ( 9) 49 ( 9) 24 ( 4) < 1% < 1% < 1% Psychiatric disorders Insomnia 147 (28) 127 (24) 53 ( 10) < 1% 6 ( 1) 0 ( 0) Depression 58 (11) 46 ( 9) 30 ( 6) 10 ( 2) < 1% < 1% Vascular disorders Deep vein thrombosis c% 55 (10) 39 ( 7) 22 ( 4) 30 ( 6) 20 ( 4) 15 ( 3) Hypotension c% 51 (10) 35 ( 6) 36 ( 7) 11 ( 2) 8 ( 1) 6 ( 1) Injury, Poisoning, and Procedural Complications Fall f 43 ( 8) 25 ( 5) 25 ( 5) < 1% 6 ( 1) 6 ( 1) Contusion f 33 ( 6) 24 ( 4) 15 ( 3) < 1% < 1% 0 ( 0) Eye disorders Cataract 73 (14) 31 ( 6) < 1% 31 ( 6) 14 ( 3) < 1% Cataract subcapsular e < 5% < 5% < 5% 7 ( 1) 0 ( 0) 0 ( 0) Investigations Weight decreased 72 (14) 78 (14) 48 ( 9) 11 ( 2) < 1% < 1% Cardiac disorders Atrial fibrillation c 37 ( 7) 25 ( 5) 25 ( 5) 13 ( 2) 9 ( 2) 6 ( 1) Myocardial infarction (including acute) c ,e < 5% < 5% < 5% 10 ( 2) < 1% < 1% Renal and Urinary disorders Renal failure (including acute) c@,f 49 ( 9) 54 (10) 37 ( 7) 28 ( 5) 33 ( 6) 29 ( 5) Neoplasms benign, malignant and unspecified (Including cysts and polyps) Squamous cell carcinoma c e < 5% < 5% < 5% 8 ( 2) < 1% 0 ( 0) Basal cell carcinoma c e,f < 5% < 5% < 5% < 1% < 1% 0 ( 0) Newly Diagnosed MM - REVLIMID Maintenance Therapy Following Auto-HSCT: Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for REVLIMID treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the REVLIMID arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm. For REVLIMID, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of REVLIMID were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2. The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment. Table 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms. Table 5: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the REVLIMID Vs Placebo Arms* Note : Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent AEs in at least 5% of patients in the REVLIMID Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. b All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. c All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study @ - ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): Pneumonias Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis Sepsis : Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy : Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis : Deep vein thrombosis, Thrombosis, Venous thrombosis Body System Adverse Reaction Maintenance Study 1 Maintenance Study 2 All Adverse Reactions a Grade 3/4 Adverse Reactions b All Adverse Reactions a Grade 3/4 Adverse Reactions b REVLIMID (N=224) n (%) Placebo (N=221) n (%) REVLIMID (N=224) n (%) Placebo (N=221) n (%) REVLIMID (N=293) n (%) Placebo (N=280) n (%) REVLIMID (N=293) n (%) Placebo (N=280) n (%) Blood and lymphatic system disorders Neutropenia c % 177 ( 79) 94 ( 43) 133 ( 59) 73 ( 33) 178 ( 61) 33 ( 12) 158 ( 54) 21 ( 8) Thrombocytopenia c % 162 ( 72) 101 ( 46) 84 ( 38) 67 ( 30) 69 ( 24) 29 ( 10) 38 ( 13) 8 ( 3) Leukopenia c 51 ( 23) 25 ( 11) 45 ( 20) 22 ( 10) 93 ( 32) 21 ( 8) 71 ( 24) 5 ( 2) Anemia 47 ( 21) 27 ( 12) 23 ( 10) 18 ( 8) 26 ( 9) 15 ( 5) 11 ( 4) 3 ( 1) Lymphopenia 40 ( 18) 29 ( 13) 37 ( 17) 26 ( 12) 13 ( 4) 3 ( 1) 11 ( 4) < 1% Pancytopenia c d % < 1% 0 ( 0) 0 ( 0) 0 ( 0) 12 ( 4) < 1% 7 ( 2) < 1% Febrile neutropenia c 39 ( 17) 34 ( 15) 39 ( 17) 34 ( 15) 7 ( 2) < 1% 5 ( 2) < 1% Infections and infestations # Upper respiratory tract infection e 60 ( 27) 35 ( 16) 7 ( 3) 9 ( 4) 32 ( 11) 18 ( 6) < 1% 0 ( 0) Neutropenic infection 40 ( 18) 19 ( 9) 27 ( 12) 14 ( 6) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) Pneumonias * c % 31 ( 14) 15 ( 7) 23 ( 10) 7 ( 3) 50 ( 17) 13 ( 5) 27 ( 9) 5 ( 2) Bronchitis c 10 ( 4) 9 ( 4) < 1% 5 ( 2) 139 ( 47) 104 ( 37) 4 ( 1) < 1% Nasopharyngitis e 5 ( 2) < 1% 0 ( 0) 0 ( 0) 102 ( 35) 84 ( 30) < 1% 0 ( 0) Gastroenteritis c 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 66 ( 23) 55 ( 20) 6 ( 2) 0 ( 0) Rhinitis e < 1% 0 ( 0) 0 ( 0) 0 ( 0) 44 ( 15) 19 ( 7) 0 ( 0) 0 ( 0) Sinusitis e 8 ( 4) 3 ( 1) 0 ( 0) 0 ( 0) 41 ( 14) 26 ( 9) 0 ( 0) < 1% Influenza c 8 ( 4) 5 ( 2) < 1% < 1% 39 ( 13) 19 ( 7) 3 ( 1) 0 ( 0) Lung infection c 21 ( 9) < 1% 19 ( 8) < 1% 9 ( 3) 4 ( 1) < 1% 0 ( 0) Lower respiratory tract infection e 13 ( 6) 5 ( 2) 6 ( 3) 4 ( 2) 4 ( 1) 4 ( 1) 0 ( 0) < 1% Infection c 12 ( 5) 6 ( 3) 9 ( 4) 5 ( 2) 17 ( 6) 5 ( 2) 0 ( 0) 0 ( 0) Urinary tract infection c d e 9 ( 4) 5 ( 2) 4 ( 2) 4 ( 2) 22 ( 8) 17 ( 6) < 1% 0 ( 0) Lower respiratory tract infection bacterial d 6 ( 3) < 1% 4 ( 2) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) Bacteremia d 5 ( 2) 0 ( 0) 4 ( 2) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) Herpes zoster c d 11 ( 5) 10 ( 5) 3 ( 1) < 1% 29 ( 10) 25 ( 9) 6 ( 2) < 1% Sepsis * c d @ < 1% < 1% 0 ( 0) 0 ( 0) 6 ( 2) < 1% 4 ( 1) < 1% Gastrointestinal disorders Diarrhea 122 ( 54) 83 ( 38) 22 ( 10) 17 ( 8) 114 ( 39) 34 ( 12) 7 ( 2) 0 ( 0) Nausea e 33 ( 15) 22 ( 10) 16 ( 7) 10 ( 5) 31 ( 11) 28 ( 10) 0 ( 0) 0 ( 0) Vomiting 17 ( 8) 12 ( 5) 8 ( 4) 5 ( 2) 16 ( 5) 15 ( 5) < 1% 0 ( 0) Constipation e 12 ( 5) 8 ( 4) 0 ( 0) 0 ( 0) 37 ( 13) 25 ( 9) < 1% 0 ( 0) Abdominal pain e 8 ( 4) 7 ( 3) < 1% 4 ( 2) 31 ( 11) 15 ( 5) < 1% < 1% Abdominal pain upper e 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 20 ( 7) 12 ( 4) < 1% 0 ( 0) General disorders and administration site conditions Asthenia 0 ( 0) < 1% 0 ( 0) 0 ( 0) 87 ( 30) 53 ( 19) 10 ( 3) < 1% Fatigue 51 ( 23) 30 ( 14) 21 ( 9) 9 ( 4) 31 ( 11) 15 ( 5) 3 ( 1) 0 ( 0) Pyrexia e 17 ( 8) 10 ( 5) < 1% < 1% 60 ( 20) 26 ( 9) < 1% 0 ( 0) Skin and subcutaneous tissue disorders Dry skin e 9 ( 4) 4 ( 2) 0 ( 0) 0 ( 0) 31 ( 11) 21 ( 8) 0 ( 0) 0 ( 0) Rash 71 ( 32) 48 ( 22) 11 ( 5) 5 ( 2) 22 ( 8) 17 ( 6) 3 ( 1) 0 ( 0) Pruritus 9 ( 4) 4 ( 2) 3 ( 1) 0 ( 0) 21 ( 7) 25 ( 9) < 1% 0 ( 0) Nervous system disorders Paresthesia e < 1% 0 ( 0) 0 ( 0) 0 ( 0) 39 ( 13) 30 ( 11) < 1% 0 ( 0) Peripheral neuropathy * e 34 ( 15) 30 ( 14) 8 ( 4) 8 ( 4) 29 ( 10) 15 ( 5) 4 ( 1) < 1% Headache d 11 ( 5) 8 ( 4) 5 ( 2) < 1% 25 ( 9) 21 ( 8) 0 ( 0) 0 ( 0) Investigations Alanine aminotransferase increased 16 ( 7) 3 ( 1) 8 ( 4) 0 ( 0) 5 ( 2) 5 ( 2) 0 ( 0) < 1% Aspartate aminotransferase increased d 13 ( 6) 5 ( 2) 6 ( 3) 0 ( 0) < 1% 5 ( 2) 0 ( 0) 0 ( 0) Metabolism and nutrition disorders Hypokalemia 24 ( 11) 13 ( 6) 16 ( 7) 12 ( 5) 12 ( 4) < 1% < 1% 0 ( 0) Dehydration 9 ( 4 ) 5 ( 2) 7 ( 3) 3 ( 1) 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) Hypophosphatemia d 16 ( 7) 15 ( 7) 13 ( 6) 14 ( 6) 0 ( 0) < 1% 0 ( 0) 0 ( 0) Musculoskeletal and connective tissue disorders Muscle spasms e 0 ( 0) < 1% 0 ( 0) 0 ( 0) 98 ( 33) 43 ( 15) < 1% 0 ( 0) Myalgia e 7 ( 3) 8 ( 4) 3 ( 1) 5 ( 2) 19 ( 6) 12 ( 4) < 1% < 1% Musculoskeletal pain e < 1% < 1% 0 ( 0) 0 ( 0) 19 ( 6) 11 ( 44) 0 ( 0) 0 ( 0) Hepatobiliary disorders Hyperbilirubinemia e 34 ( 15) 19 ( 9) 4 ( 2) < 1% 4 ( 1) < 1% < 1% 0 ( 0) Respiratory, thoracic and mediastinal disorders Cough e 23 ( 10) 12 ( 5) 3 ( 1) < 1% 80 ( 27) 56 ( 20) 0 ( 0) 0 ( 0) Dyspnea c e 15 ( 7) 9 ( 4) 8 ( 4) 4 ( 2) 17 ( 6) 9 ( 3) < 1% 0 ( 0) Rhinorrhea e 0 ( 0) 3 ( 1) 0 ( 0) 0 ( 0) 15 ( 5) 6 ( 2) 0 ( 0) 0 ( 0) Pulmonary embolism c d e 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) 3 ( 1) 0 ( 0) < 1% 0 ( 0) Vascular disorders Deep vein thrombosis *c d % 8 ( 4) < 1% 5 ( 2) < 1% 7 ( 2) < 1% 4 ( 1) < 1% Neoplasms benign, malignant and unspecified (including cysts and polyps) Myelodysplastic syndrome c d e 5 ( 2) 0 ( 0) < 1% 0 ( 0) 3 ( 1) 0 ( 0) < 1% 0 ( 0) After At Least One Prior Therapy for MM: Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone. Tables 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups. Table 6: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups Body System Adverse Reaction REVLIMID/Dex (N=353) n (%) Placebo/Dex (N=350) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42) 22 ( 6) Anemia @ 111 (31) 83 (24) Thrombocytopenia @ 76 (22) 37 (11) Leukopenia 28 ( 8) 4 ( 1) Lymphopenia 19 ( 5) 5 ( 1) General disorders and administration site conditions Fatigue 155 (44) 146 (42) Pyrexia 97 (27) 82 (23) Peripheral edema 93 (26) 74 (21) Chest pain 29 ( 8) 20 ( 6) Lethargy 24 ( 7) 8 ( 2) Gastrointestinal disorders Constipation 143 (41) 74 (21) Diarrhea @ 136 (39) 96 (27) Nausea @ 92 (26) 75 (21) Vomiting @ 43 (12) 33 ( 9) Abdominal pain @ 35 ( 10) 22 ( 6) Dry mouth 25 ( 7) 13 ( 4) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33) 74 (21) Back pain 91 (26) 65 (19) Bone pain 48 (14) 39 (11) Pain in limb 42 (12) 32 ( 9) Nervous system disorders Dizziness 82 (23) 59 (17) Tremor 75 (21) 26 ( 7) Dysgeusia 54 (15) 34 ( 10) Hypoesthesia 36 (10) 25 ( 7) Neuropathy a 23 ( 7) 13 ( 4) Respiratory, thoracic and mediastinal disorders Dyspnea 83 (24) 60 (17) Nasopharyngitis 62 (18) 31 ( 9) Pharyngitis 48 (14) 33 ( 9) Bronchitis 40 (11) 30 ( 9) Infections b and infestations Upper respiratory tract infection 87 (25) 55 (16) Pneumonia @ 48 (14) 29 ( 8) Urinary tract infection 30 ( 8) 19 ( 5) Sinusitis 26 ( 7) 16 ( 5) Skin and subcutaneous system disorders Rash c 75 (21) 33 ( 9) Sweating increased 35 ( 10) 25 ( 7) Dry skin 33 ( 9) 14 ( 4) Pruritus 27 ( 8) 18 ( 5) Metabolism and nutrition disorders Anorexia 55 (16) 34 ( 10) Hypokalemia 48 (14) 21 ( 6) Hypocalcemia 31 ( 9) 10 ( 3) Appetite decreased 24 ( 7) 14 ( 4) Dehydration 23 ( 7) 15 ( 4) Hypomagnesemia 24 ( 7) 10 ( 3) Investigations Weight decreased 69 (20) 52 (15) Eye disorders Blurred vision 61 (17) 40 (11) Vascular disorders Deep vein thrombosis % 33 ( 9) 15 ( 4) Hypertension 28 ( 8) 20 ( 6) Hypotension 25 ( 7) 15 ( 4) Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone groups Body System Adverse Reaction REVLIMID/Dex (N=353) n (%) Placebo/Dex (N=350) n (%) Blood and lymphatic system disorders Neutropenia % 118 (33) 12 ( 3) Thrombocytopenia @ 43 (12) 22 ( 6) Anemia @ 35 ( 10) 20 ( 6) Leukopenia 14 ( 4) < 1% Lymphopenia 10 ( 3) 4 ( 1) Febrile neutropenia % 8 ( 2) 0 ( 0) General disorders and administration site conditions Fatigue 23 ( 7) 17 ( 5) Vascular disorders Deep vein thrombosis % 29 ( 8) 12 ( 3) Infections and infestations Pneumonia @ 30 ( 8) 19 ( 5) Urinary tract infection 5 ( 1) < 1% Metabolism and nutrition disorders Hypokalemia 17 ( 5) 5 ( 1) Hypocalcemia 13 ( 4) 6 ( 2) Hypophosphatemia 9 ( 3) 0 ( 0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism @ 14 ( 4) < 1% Respiratory distress @ 4 ( 1) 0 ( 0) Musculoskeletal and connective tissue disorders Muscle weakness 20 ( 6) 10 ( 3) Gastrointestinal disorders Diarrhea @ 11 ( 3) 4 ( 1) Constipation 7 ( 2) < 1% Nausea @ 6 ( 2) < 1% Cardiac disorders Atrial fibrillation @ 13 ( 4) 4 ( 1) Tachycardia 6 ( 2) < 1% Cardiac failure congestive @ 5 ( 1) < 1% Nervous system disorders Syncope 10 ( 3) < 1% Dizziness 7 ( 2) < 1% Eye disorders Cataract 6 ( 2) < 1% Cataract unilateral 5 ( 1) 0 ( 0) Psychiatric disorder Depression 10 ( 3) 6 ( 2) Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups Body System Adverse Reaction REVLIMID/Dex (N=353) n (%) Placebo/Dex (N=350) n (%) For Tables 6, 7 and 8 above: @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). Blood and lymphatic system disorders Febrile neutropenia % 6 ( 2) 0 ( 0) Vascular disorders Deep vein thrombosis % 26 ( 7) 11 ( 3) Infections and infestations Pneumonia @ 33 ( 9) 21 ( 6) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism @ 13 ( 4) < 1% Cardiac disorders Atrial fibrillation @ 11 ( 3) < 1% Cardiac failure congestive @ 5 ( 1) 0 ( 0) Nervous system disorders Cerebrovascular accident @ 7 ( 2) < 1% Gastrointestinal disorders Diarrhea @ 6 ( 2) < 1% Musculoskeletal and connective tissue disorders Bone pain 4 ( 1) 0 ( 0) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone. Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.4) ] VTE and ATE are increased in patients treated with REVLIMID. Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively). Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation Myelodysplastic Syndromes: A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions . Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient's underlying disease. Table 9: Summary of Adverse Reactions Reported in ≥5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study a Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. Body System Adverse Reaction a 10 mg Overall (N=148) Patients with at least one adverse reaction 148 (100) Blood and Lymphatic System Disorders Thrombocytopenia 91 (61) Neutropenia 87 (59) Anemia 17 (11) Leukopenia 12 (8) Febrile Neutropenia 8 (5) Skin and Subcutaneous Tissue Disorders Pruritus 62 (42) Rash 53 (36) Dry Skin 21 (14) Contusion 12 (8) Night Sweats 12 (8) Sweating Increased 10 (7) Ecchymosis 8 (5) Erythema 8 (5) Gastrointestinal Disorders Diarrhea 72 (49) Constipation 35 (24) Nausea 35 (24) Abdominal Pain 18 (12) Vomiting 15 (10) Abdominal Pain Upper 12 (8) Dry Mouth 10 (7) Loose Stools 9 (6) Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis 34 (23) Cough 29 (20) Dyspnea 25 (17) Pharyngitis 23 (16) Epistaxis 22 (15) Dyspnea Exertional 10 (7) Rhinitis 10 (7) Bronchitis 9 (6) General Disorders and Administration Site Conditions Fatigue 46 (31) Pyrexia 31 (21) Edema Peripheral 30 (20) Asthenia 22 (15) Edema 15 (10) Pain 10 (7) Rigors 9 (6) Chest Pain 8 (5) Musculoskeletal and Connective Tissue Disorders Arthralgia 32 (22) Back Pain 31 (21) Muscle Cramp 27 (18) Pain in Limb 16 (11) Myalgia 13 (9) Peripheral Swelling 12 (8) Nervous System Disorders Dizziness 29 (20) Headache 29 (20) Hypoesthesia 10 (7) Dysgeusia 9 (6) Peripheral Neuropathy 8 (5) Infections and Infestations Upper Respiratory Tract Infection 22 (15) Pneumonia 17 (11) Urinary Tract Infection 16 (11) Sinusitis 12 (8) Cellulitis 8 (5) Metabolism and Nutrition Disorders Hypokalemia 16 (11) Anorexia 15 (10) Hypomagnesemia 9 (6) Investigations Alanine Aminotransferase Increased 12 (8) Psychiatric Disorders Insomnia 15 (10) Depression 8 (5) Renal and Urinary Disorders Dysuria 10 (7) Vascular Disorders Hypertension 9 (6) Endocrine Disorders Acquired Hypothyroidism 10 (7) Cardiac Disorders Palpitations 8 (5) Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions 1 Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study 1 Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. 2 Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Adverse Reactions 2 10 mg (N=148) Patients with at least one Grade 3/4 AE 131 (89) Neutropenia 79 (53) Thrombocytopenia 74 (50) Pneumonia 11 (7) Rash 10 (7) Anemia 9 (6) Leukopenia 8 (5) Fatigue 7 (5) Dyspnea 7 (5) Back Pain 7 (5) Febrile Neutropenia 6 (4) Nausea 6 (4) Diarrhea 5 (3) Pyrexia 5 (3) Sepsis 4 (3) Dizziness 4 (3) Granulocytopenia 3 (2) Chest Pain 3 (2) Pulmonary Embolism 3 (2) Respiratory Distress 3 (2) Pruritus 3 (2) Pancytopenia 3 (2) Muscle Cramp 3 (2) Respiratory Tract Infection 2 (1) Upper Respiratory Tract Infection 2 (1) Asthenia 2 (1) Multi-organ Failure 2 (1) Epistaxis 2 (1) Hypoxia 2 (1) Pleural Effusion 2 (1) Pneumonitis 2 (1) Pulmonary Hypertension 2 (1) Vomiting 2 (1) Sweating Increased 2 (1) Arthralgia 2 (1) Pain in Limb 2 (1) Headache 2 (1) Syncope 2 (1) In other clinical studies of REVLIMID in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported: Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction Ear and labyrinth disorders: vertigo Endocrine disorders: Basedow's disease Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure Immune system disorders: hypersensitivity Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack Psychiatric disorders: confusional state Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass Reproductive system and breast disorders: pelvic pain Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis Mantle Cell Lymphoma: In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions. Table 11: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma 1 -MCL trial AEs – All treatment emergent AEs with ≥10% of subjects. 2 -MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects. $ -MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects. @ - Adverse reactions where at least one resulted in a fatal outcome. % - Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases). # - All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed. + - All adverse reactions under HLT of Rash will be considered listed. Body System Adverse Reaction All Adverse Reactions 1 (N=134) n (%) Grade 3/4 Adverse Reactions 2 (N=134) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia $ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia $ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea $ 42 (31) 8 (6) Nausea $ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting $ 16 (12) 1 (<1) Abdominal pain $ 13 (10) 5 ( 4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness $ 8 (6) 2 ( 1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea $ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 ( 1) Respiratory distress $ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia @ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis $ 3 (2) 2 (1) Bacteremia $ 2 (1) 2 (1) Staphylococcal sepsis $ 2 (1) 2 (1) Urinary tract infection $ 5 (4) 2 (1) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia % $ 48 (36) 37 (28) Anemia $ 41 (31) 15 (11) Leukopenia $ 20 (15) 9 (7) Lymphopenia 10 ( 7) 5 (4) Febrile neutropenia $ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration $ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure $ 5 (4) 2 (1) Vascular disorders Hypotension @ $ 9 (7) 4 (3) Deep vein thrombosis $ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin $ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. Cardiac disorder: Cardiac failure Ear and labyrinth disorders: Vertigo General disorders and administration site conditions: Chills Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy Psychiatric disorders: Insomnia Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse reactions not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Blood and lymphatic system disorders: Neutropenia Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia Infections and infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism Follicular Lymphoma or Marginal Zone Lymphoma The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N=176) and MAGNIFY (N=222) [see Clinical Studies (14.4) ] . Subjects were 18 years or older in age, had an ECOG PS ≤2, ANC ≥1,000 cells/mm 3 and platelets≥ 75,000/mm 3 (unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥8g/dL, AST and ALT ≤ 3 x ULN (unless documented liver involvement with lymphoma, and creatinine clearance of ≥ 30mL/min. Subjects with active HIV, hepatitis B or C were not eligible. In the AUGMENT trial, patients received REVLIMID 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=176) or placebo with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=180) for up to 12 cycles. In the MAGNIFY trial, patients received REVLIMID 20 mg by mouth daily, days 1-21 of each 28 day cycle with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 5, 7, 9 and 11 in the induction phase of the trial (n=222). In the AUGMENT trial, 88.1% of patients completed at least 6 cycles of REVLIMID/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6 cycles of REVLIMID/rituximab, and 30.6% of patients completed 12 cycles. Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White. Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving REVLIMID/rituximab in AUGMENT and 29% in MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was neutropenia (4.8%). The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%). Table 12: All Grade Adverse Reactions ( ≥5%) or Grade 3/4 Adverse Reactions ( ≥1%) in Patients with FL and MZL with a Difference Between Arms of >1% When Compared to Control Arm in AUGMENT Trial Note : Adverse reactions are coded to body system/adverse reaction using MedDRA 21. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse reaction. 1 All treatment-emergent AEs in at least 5% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 2 All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 3 All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). $ Serious ADR reported. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]): a "Thromboembolic events" combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis. b "Cough" combined AE term includes the following PTs: cough and productive cough. c “Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper. d "Rash" combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and rash generalized. e "Pruritus" combined AE term includes the following PTs: pruritus, pruritus generalized, rash pruritic, and pruritus allergic. All Adverse Reactions 1 Grade 3 / 4 Adverse Reactions 2 Body System Adverse Reaction * REVLIMID + Rituximab Arm (N=176) n (%) Rituximab + Placebo (Control Arm) (N=180) n (%) REVLIMID + Rituximab Arm (N=176) n (%) Rituximab + Placebo (Control Arm) (N=180) n (%) Infections and infestations Upper respiratory tract infection 32 (18) 23 (13) 2 (1.1) 4 (2.2) Influenza % 17 (10) 8 (4.4) 1 (< 1) 0 (0) Pneumonia 3,$,% 13 (7) 6 (3.3) 6 (3.4) 4 (2.2) Sinusitis 13 (7) 5 (2.8) 0 (0) 0 (0) Urinary tract infection $ 13 (7) 7 (3.9) 1 (< 1) 1 (< 1) Bronchitis 8 (4.5) 6 (3.3) 2 (1.1) 0 (0) Gastroenteritis $ 6 (3.4) 4 (2.2) 2 (1.1) 0 (0) Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumor flare $ 19 (11) 1 (< 1) 1 (< 1) 0 (0) Blood and lymphatic disorders Neutropenia 3,$, % 102 (58) 40 (22) 88 (50) 23 (13) Leukopenia $,% 36 (20) 17 (9) 12 (7) 3 (1.7) Anemia 3,$ 28 (16) 8 (4.4) 8 (4.5) 1 (< 1) Thrombocytopenia 3,$,% 26 (15) 8 (4.4) 4 (2.3) 2 (1.1) Lymphopenia 8 (4.5) 14 (8) 5 (2.8) 2 (1.1) Febrile Neutropenia 3,$,% 5 (2.8) 1 (< 1) 5 (2.8) 1 (< 1) Metabolism and nutrition disorders Decreased Appetite 23 (13) 11 (6) 2 (1.1) 0 (0) Hypokalemia % 14 (8) 5 (2.8) 4 (2.3) 0 (0) Hyperuricemia 10 (6) 8 (4.4) 1 (< 1) 1 (< 1) Nervous system disorders Headache 26 (15) 17 (9) 1 (< 1) 0 (0) Dizziness 15 (9) 9 (5) 0 (0) 0 (0) Vascular disorders Hypotension % 9 (5) 1 (< 1) 1 (< 1) 0 (0) Thromboembolic events a,$ 8 (4.5) 2 (1.1) 4 (2.3) 2 (1.1) Respiratory, thoracic and mediastinal disorders Cough b 43 (24) 35 (19) 1 (< 1) 0 (0) Dyspnea $ 19 (11) 8 (4.4) 2 (1.1) 1 (< 1) Oropharyngeal pain 10 (6) 8 (4.4) 0 (0) 0 (0) Pulmonary Embolism 3,$ 4 (2.3) 1 (< 1) 4 (2.3) 1 (< 1) Chronic obstructive pulmonary disease $ 3 (1.7) 0 (0) 2 (1.1) 0 (0) Respiratory failure 3,$ 2 (1.1) 1 (< 1) 2 (1.1) 0 (0) Gastrointestinal disorders Diarrhea $,% 55 (31) 41 (23) 5 (2.8) 0 (0) Constipation 46 (26) 25 (14) 0 (0) 0 (0) Abdominal pain c ,$ 32 (18) 20 (11) 2 (1.1) 0 (0) Vomiting $ 17 (10) 13 (7) 0 (0) 0 (0) Dyspepsia 16 (9) 5 (2.8) 0 (0) 0 (0) Stomatitis 9 (5) 7 (3.9) 0 (0) 0 (0) Skin and subcutaneous tissue disorders Rash $,d 39 (22) 14 (8) 5 (2.8) 2 (1.1) Pruritus $,e 36 (20) 9 (5) 2 (1.1) 0 (0) Dry skin 9 (5) 6 (3.3) 0 (0) 0 (0) Dermatitis acneiform 8 (4.5) 0 (0) 2 (1.1) 0 (0) Musculoskeletal and connective tissue disorders Muscle Spasms 23 (13) 9 (5) 1 (< 1) 1 (< 1) Pain in Extremity $ 8 (4.5) 9 (5) 2 (1) 0 (0) Renal disorders Acute Kidney Injury 3,$,@,% 3 (1.7) 0 (0) 2 (1.1) 0 (0) Cardiac disorders Supraventricular tachycardia 3,$ 2 (1.1) 0 (0) 2 (1.1) 0 (0) General disorders and administration site conditions Fatigue 38 (22) 33 (18) 2 (1.1) 1 (< 1) Pyrexia 3,$ 37 (21) 27 (15) 1 (< 1) 3 (1.7) Asthenia $,% 24 (14) 19 (11) 2 (1.1) 1 (< 1) Edema Peripheral $ 23 (13) 16 (9) 0 (0) 0 (0) Chills 14 (8) 8 (4.4) 0 (0) 0 (0) Malaise 13 (7) 10 (6) 0 (0) 0 (0) Influenza like illness 9 (5) 7 (3.9) 0 (0) 0 (0) Psychiatric disorders Insomnia 14 (8) 11 (6) 0 (0) 0 (0) Investigations Alanine Aminotransferase Increased 18 (10) 15 (8) 3 (1.7) 1 (< 1) WBC count decreased 16 (9) 13 (7) 5 (2.8) 2 (1.1) Lymphocyte count decreased 12 (7) 12 (7) 6 (3.4) 2 (1.1) Blood bilirubin increased 10 (6) 0 (0) 0 (0) 0 (0) Weight Decreased 12 (7) 2 (1.1) 0 (0) 0 (0) 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.8 to 5.11 , and 5.13) ] Endocrine disorders: Hypothyroidism, hyperthyroidism Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests Immune system disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML) Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

• Digoxin: Monitor digoxin plasma levels periodically due to increased C max and AUC with concomitant REVLIMID therapy ( 7.1 ).
• Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with REVLIMID may increase the risk of thrombosis ( 7.2 ). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin C max and AUC inf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4) ] . 7.3 Warfarin Co-administration of multiple doses of REVLIMID (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action and findings from animal studies , REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy . REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats . 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 risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis.

Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation.

The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20-40% of the maternal C max.

Following a single oral dose to pregnant rats, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues. These data indicated that lenalidomide crossed the placenta.

Pediatric Use Safety and effectiveness have not been established in pediatric patients.

• Pregnancy ( Boxed Warning , 4.1 , 5.1 , 8.1 ).
• Demonstrated severe hypersensitivity to lenalidomide ( 4.2 , 5.9 , 5.15 ). 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide's structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning ]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus [see Warnings and Precautions (5.1 , 5.2) , Use in Special Populations (8.1 , 8.3) ] . 4.2 Severe Hypersensitivity Reactions REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.9 , 5.15 )].

There is no specific experience in the management of REVLIMID overdose in patients with MM, MDS, MCL, FL, or MZL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.