ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)] Hematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)] Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] Second Primary Malignancies [see Warnings and Precautions (5.6)] Increased Mortality in Patients with MM When Pembrolizumab Is Added to Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7)] Hepatotoxicity [see Warnings and Precautions (5.8)] Severe Cutaneous Reactions [see Warnings and Precautions (5.9)] Tumor Lysis Syndrome [see Warnings and Precautions (5.10)] Tumor Flare Reactions [see Warnings and Precautions (5.11)] Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12)] Thyroid Disorders [see Warnings and Precautions (5.13)] Early Mortality in Patients with MCL [see Warnings and Precautions (5.14)] Hypersensitivity [see Warnings and Precautions (5.15)]. Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)] Hematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)] Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] Second Primary Malignancies [see Warnings and Precautions (5.6)] Increased Mortality in Patients with MM When Pembrolizumab Is Added to Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7)] Hepatotoxicity [see Warnings and Precautions (5.8)] Severe Cutaneous Reactions [see Warnings and Precautions (5.9)] Tumor Lysis Syndrome [see Warnings and Precautions (5.10)] Tumor Flare Reactions [see Warnings and Precautions (5.11)] Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12)] Thyroid Disorders [see Warnings and Precautions (5.13)] Early Mortality in Patients with MCL [see Warnings and Precautions (5.14)] 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-Hodgkins Lymphoma (NHL: MCL): 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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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-Hodgkins Lymphoma (NHL: MCL): Most common adverse reactions (>=15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash (6.1).. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 Lenalidomide Capsules Combination Therapy:Data were evaluated from 1613 patients in large phase study who received at least one dose of lenalidomide with low dose dexamethasone (Rd) given for 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 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 or 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 and 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 lenalidomide were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was weeks. The most common adverse reactions leading to dose reduction of lenalidomide in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 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 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.Table 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 ArmsBody SystemAdverse ReactionAll Adverse Reactionsa Grade 3/4 Adverse Reactionsb 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) Pyrexiac 114 (21)102 (19)76 (14)13 (2)7 (1)7 (1) Non-cardiac chest painf 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% Dyspepsiaf 57 (11)28 (5)36 (7)<1%< 1%0 (0)Musculoskeletal and connective tissue disorders Back painc 170 (32)145 (27)116 (21)37 (7)34 (6)28 (5) Muscle spasmsf 109 (20)102 (19)61 (11)< 1%< 1%< 1% Arthralgiaf 101 (19)71 (13)66 (12)9 (2)8 (1)8 (1) Bone painf 87 (16)77 (14)62 (11)16 (3)15 (3)14 (3) Pain in extremityf 79 (15)66 (12)61 (11)8 (2)8 (1)7 (1) Musculoskeletal painf 67 (13)59 (11)36 (7)< 1%< 1%< 1% Musculoskeletal chest painf 60 (11)51 (9)39 (7)6 (1)< 1%< 1% Muscular weaknessf 43 (8)35 (6)29 (5)< 1%8 (1)< 1% Neck painf 40 (8)19 (4)10 (2)< 1%< 1%< 1%Infections and infestations Bronchitisc 90 (17)59 (11)43 (8)9 (2)6 (1)< 1% Nasopharyngitisf 80 (15)54 (10)33 (6)0 (0)0 (0)0 (0) Urinary tract infectionf 76 (14)63 (12)41 (8)8 (2)8 (1)< 1% Upper respiratory tract infectionc% 69 (13)53 (10)31 (6)< 1%8 (1)< 1% Pneumoniac 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% Influenzaf 33 (6)23 (4)15 (3)< 1%< 1%0 (0) Gastroenteritisf 32 (6)17 (3)13 (2)0 (0)< 1%< 1% Lower respiratory tract infection 29 (5)14 (3)16 (3)10 (2)< 1%< 1% Rhinitisf 29 5)24 (4)14 (3)0 (0)0 (0)0 (0) Cellulitisc 5%< 5%< 5%8 (2)< 1%< 1% Sepsisc 33 (6)26 (5)18 (3)26 (5)20 (4)13 (2)Nervous system disorders Headachef 75 (14)52 (10)56 (10)< 1%< 1%< 1% Dysgeusiaf 39 (7)45 (8)22 (4)< 1%0 (0.0)< 1%Blood and lymphatic system disordersd 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 (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 Coughf 121 (23)94 (17)68 (13)< 1%< 1%< 1% Dyspneac,e 117 (22)89 (16)113 (21)30 (6)22 (4)18 (3) Epistaxisf 32 (6)31 (6)17 (3)< 1%< 1%0 (0) Oropharyngeal painf 30 (6)22 (4)14 (3)0 (0)0 (0)0 (0) Dyspnea exertionale 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) Hypocalcemia57 (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 < 5%< 5%< 5%8 (2)0 (0)0 (0) Diabetes mellitus% < 5%< 5%< 5%8 (2)< 1%< 1% Hypophosphatemiae 5%< 5%< 5%7 (1)< 1%< 1% Hyponatremia% < 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 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 thrombosisc 55 (10)39 (7)22 (4)30 (6)20 (4)15 (3) Hypotensionc 51 (10)35 (6)36 (7)11 (2)8 (1)6 (1)Injury, Poisoning, and Procedural Complications Fallf 43 (8)25 (5)25 (5)< 1%6 (1)6 (1) Contusionf 33 (6)24 (4)15 (3)< 1%< 1%0 (0)Eye disorders Cataract 73 (14)31 (6)< 1%31 (6)14 (3)< 1% Cataract subcapsulare 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 fibrillationc 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 carcinomac < 5%< 5%< 5%8 (2)< 1%0 (0) Basal cell carcinomac e,f 5%< 5%< 5%< 1%< 1%0 (0)Note: 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 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm.b All grade or treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least 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 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. Footnote b not applicable. adverse reactions in which at least one resulted in 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 sepsisRash: 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 pustularDeep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosisAfter At Least One Prior Therapy for MM:Data were evaluated from 703 patients in two studies who received at least one dose of lenalidomide/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the lenalidomide/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without dose reduction of lenalidomide compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without dose reduction, 50% in the lenalidomide/dexamethasone treatment group had at least one additional dose interruption with or without 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 lenalidomide/dexamethasone compared to placebo/dexamethasone. Tables 6, 7, and summarize the adverse reactions reported for lenalidomide/dexamethasone and placebo/dexamethasone groups.Table 6: Adverse Reactions Reported in >=5% of Patients and with >=2% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone GroupsBody System Adverse ReactionLenalidomide/Dex(N=353)n (%)Placebo/Dex(N=350)n (%)Blood and lymphatic system disordersNeutropenia% 149 (42)22 (6)Anemia 111 (31)83 (24)Thrombocytopenia 76 (22)37 (11)Leukopenia 28 (8)4 (1)Lymphopenia19 (5)5 (1)General disorders and administration site conditionsFatigue 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 disordersMuscle 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 disordersDizziness 82 (23)59 (17)Tremor 75 (21)26 (7)Dysgeusia 54 (15)34 (10)Hypoesthesia36 (10)25 (7)Neuropathya 23 (7)13 (4)Respiratory, thoracic and mediastinal disordersDyspnea 83 (24)60 (17)Nasopharyngitis62 (18)31 (9)Pharyngitis 48 (14)33 (9)Bronchitis 40 (11)30 (9)Infectionsb and infestationsUpper 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 disordersRashc 75 (21)33 (9)Sweating increased 35 (10)25 (7)Dry skin 33 (9)14 (4)Pruritus 27 (8)18 (5)Metabolism and nutrition disordersAnorexia 55 (16)34 (10)Hypokalemia 48 (14)21 (6)Hypocalcemia31 (9)10 (3)Appetite decreased 24 (7)14 (4)Dehydration 23 (7)15 (4)Hypomagnesemia24 (7)10 (3)InvestigationsWeight decreased 69 (20)52 (15)Eye disordersBlurred vision 61 (17)40 (11)Vascular disordersDeep 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 >=1% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone groupsBody SystemAdverse ReactionLenalidomide/Dex(N=353)n (%)Placebo/Dex(N=350)n (%)Blood and lymphatic system disordersNeutropenia% 118 (33)12 (3)Thrombocytopenia 43 (12)22 (6)Anemia 35 (10)20 (6)Leukopenia14 (4)< 1%Lymphopenia10 (3)4 (1)Febrile neutropenia% (2)0 (0)General disorders and administration site conditionsFatigue23 (7)17 (5)Vascular disordersDeep vein thrombosis% 29 (8)12 (3)Infections and infestationsPneumonia 30 (8)19 (5)Urinary tract infection5 (1)< 1%Metabolism and nutrition disordersHypokalemia17 (5)5 (1)Hypocalcemia13 (4)6 (2)Hypophosphatemia9 (3)0 (0)Respiratory, thoracic and mediastinal disordersPulmonary embolism 14 (4)< 1%Respiratory distress (1)0 (0)Musculoskeletal and connective tissue disordersMuscle weakness20 (6)10 (3)Gastrointestinal disordersDiarrhea 11 (3)4 (1)Constipation7 (2)< 1%Nausea (2)< 1%Cardiac disordersAtrial fibrillation 13 (4)4 (1)Tachycardia6 (2)< 1%Cardiac failure congestive (1)< 1%Nervous system disorders Syncope10 (3)< 1%Dizziness7 (2)< 1%Eye disordersCataract6 (2)< 1%Cataract unilateral5 (1)0 (0)Psychiatric disorderDepression10 (3)6 (2)Table 8: Serious Adverse Reactions Reported in >=1% Patients and with >=1% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone GroupsBody SystemAdverse ReactionLenalidomide/Dex(N=353)n (%)Placebo/Dex(N=350)n (%)Blood and lymphatic system disordersFebrile neutropenia% (2)0 (0)Vascular disordersDeep vein thrombosis% 26 (7)11 (3)Infections and infestationsPneumonia 33 (9)21 (6)Respiratory, thoracic, and mediastinal disordersPulmonary embolism 13 (4)< 1%Cardiac disordersAtrial fibrillation 11 (3)< 1%Cardiac failure congestive (1)0 (0)Nervous system disordersCerebrovascular accident (2)< 1%Gastrointestinal disordersDiarrhea (2)< 1%Musculoskeletal and connective tissue disordersBone pain4 (1)0 (0)For Tables 6, and above: adverse reactions in which at least one resulted in 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).Median duration of exposure among patients treated with lenalidomide/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 lenalidomide/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 lenalidomide capsules.Deep vein thrombosis (DVT) was reported as serious (7.4%) or severe (8.2%) adverse drug reaction at higher rate in the lenalidomide/dexamethasone group compared to 3.1 and 3.4% in the placebo/dexamethasone group, respectively in the studies in patients with at least 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 serious adverse reaction (3.6%, 2.0%, 1.7%), and as 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 lenalidomide 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 serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at higher rate in the lenalidomide/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the studies in patients with, at least 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 serious (1.7%) or severe (1.7%) adverse drug reaction at higher rate in the lenalidomide/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 lenalidomide/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 serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as serious (2.3%) or severe (2.0%) adverse drug reaction in the lenalidomide/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in lenalidomide/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 serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as 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 MMIn these 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: hirsutismEye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodyniaGeneral 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 hyperpigmentationMyelodysplastic Syndromes: total of 148 patients received at least dose of 10 mg lenalidomide 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 lenalidomide capsules. 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 summarizes the adverse reactions that were reported in >= 5% of the lenalidomide treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade and Grade adverse reactions regardless of relationship to treatment with lenalidomide. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patients underlying disease.Table 9: Summary of Adverse Reactions Reported in >=5% of the Lenalidomide Treated Patients in del 5q MDS Clinical StudyBody SystemAdverse Reaction 10 mg Overall(N=148)Patients with at least one adverse reaction148(100)Blood and Lymphatic System Disorders Thrombocytopenia91(61) Neutropenia87(59) Anemia17(11) Leukopenia12(8) Febrile Neutropenia8(5)Skin and Subcutaneous Tissue Disorders Pruritus62(42) Rash53(36) Dry Skin21(14) Contusion12(8) Night Sweats12(8) Sweating Increased10(7) Ecchymosis8(5) Erythema8(5)Gastrointestinal Disorders Diarrhea72(49) Constipation35(24) Nausea35(24) Abdominal Pain18(12) Vomiting15(10) Abdominal Pain Upper12(8) Dry Mouth10(7) Loose Stools9(6)Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis34(23) Cough29(20) Dyspnea25(17) Pharyngitis23(16) Epistaxis22(15) Dyspnea Exertional10(7) Rhinitis10(7) Bronchitis9(6)General Disorders and Administration Site Conditions Fatigue46(31) Pyrexia31(21) Edema Peripheral30(20) Asthenia22(15) Edema15(10) Pain10(7) Rigors9(6) Chest Pain8(5)Musculoskeletal and Connective Tissue Disorders Arthralgia32(22) Back Pain31(21) Muscle Cramp27(18) Pain in Limb16(11) Myalgia13(9) Peripheral Swelling12(8)Nervous System Disorders Dizziness29(20) Headache29(20) Hypoesthesia10(7) Dysgeusia9(6) Peripheral Neuropathy8(5)Infections and Infestations Upper Respiratory Tract Infection22(15) Pneumonia17(11) Urinary Tract Infection16(11) Sinusitis12(8) Cellulitis8(5)Metabolism and Nutrition Disorders Hypokalemia16(11) Anorexia15(10) Hypomagnesemia9(6)Investigations Alanine Aminotransferase Increased12(8)Psychiatric Disorders Insomnia15(10) Depression8(5)Renal and Urinary Disorders Dysuria10(7)Vascular Disorders Hypertension9(6)Endocrine Disorders Acquired Hypothyroidism10(7)Cardiac Disorders Palpitations8(5)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. patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.Table 10: Most Frequently Observed Grade and Adverse Reactions Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical StudyAdverse Reactions 10 mg(N=148)Patients with at least one Grade 3/4 AE131 (89) Neutropenia79 (53) Thrombocytopenia74 (50) Pneumonia 11 (7) Rash10 (7) Anemia9 (6) Leukopenia8 (5) Fatigue7 (5) Dyspnea (5) Back Pain7 (5) Febrile Neutropenia6 (4) Nausea6 (4) Diarrhea5 (3) Pyrexia5 (3) Sepsis (3) Dizziness (3) Granulocytopenia3 (2) Chest Pain (2) Pulmonary Embolism3 (2) Respiratory Distress3 (2) Pruritus3 (2) Pancytopenia (2) Muscle Cramp3 (2) Respiratory Tract Infection2 (1) Upper Respiratory Tract Infection2 (1) Asthenia2 (1) Multi-organ Failure2 (1) Epistaxis2 (1) Hypoxia2 (1) Pleural Effusion2 (1) Pneumonitis2 (1) Pulmonary Hypertension2 (1) Vomiting2 (1) Sweating Increased2 (1) Arthralgia2 (1) Pain in Limb2 (1) Headache2 (1) Syncope2 (1)1 Adverse reactions with frequency >=1% in the 10 mg Overall group. Grade and are based on National Cancer Institute Common Toxicity Criteria version 2.2 Adverse reactions are coded using the MedDRA dictionary. patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.In other clinical studies of lenalidomide in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 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: Basedows diseaseGastrointestinal 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, urosepsisInjury, 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 increasedMetabolism 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, wheezingSkin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosisVascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosisMantle Cell Lymphoma: In the MCL trial, total of 134 patients received at least dose of lenalidomide. Their median age was 67 (range 43 to 83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least years.Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with lenalidomide. Across the 134 patients treated in this study, median duration of treatment was 95 days (1 to 1002 days). Seventy-eight patients (58%) received or more cycles of therapy, 53 patients (40%) received 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 patients) in Mantle Cell LymphomaBody SystemAdverse ReactionAll Adverse Reactions1 (N=134)n (%)Grade 3/4 Adverse Reactions2 (N=134)n (%)General disorders and administration site conditionsFatigue45 (34)9 (7)Pyrexia 31 (23)3 (2)Edema peripheral21 (16)0Asthenia 19 (14)4 (3)General physical health deterioration3 (2)2 (1)Gastrointestinal disordersDiarrhea 42 (31)8 (6)Nausea 40 (30)1 (<1)Constipation21 (16)1 (<1)Vomiting 16 (12)1 (<1)Abdominal pain 13 (10)5 (4)Musculoskeletal and connective tissue disordersBack pain18 (13)2 (1)Muscle spasms17 (13)1 (<1)Arthralgia11 (8)2 (1)Muscular weakness (6)2 (1)Respiratory, thoracic and mediastinal disordersCough38 (28)1 (<1)Dyspnea 24 (18)8 (6)Pleural Effusion10 (7)2 (1)Hypoxia3 (2)2 (1)Pulmonary embolism3 (2)2 (1)Respiratory distress (1)2 (1)Oropharyngeal pain13 (10)0Infections and infestationsPneumonia 19 (14)12 (9)Upper respiratory tract infection17 (13)0Cellulitis (2)2 (1)Bacteremia (1)2 (1)Staphylococcal sepsis (1)2 (1)Urinary tract infection (4)2 (1)Skin and subcutaneous tissue disordersRash 30 (22)2 (1)Pruritus23 (17)1 (<1)Blood and lymphatic system disordersNeutropenia65 (49)58 (43)Thrombocytopenia% 48 (36)37 (28)Anemia 41 (31)15 (11)Leukopenia 20 (15)9 (7)Lymphopenia10 (7)5 (4)Febrile neutropenia (6)8 (6)Metabolism and nutrition disordersDecreased appetite19 (14)1 (<1)Hypokalemia17 (13)3 (2)Dehydration 10 (7)4 (3)Hypocalcemia4 (3)2 (1)Hyponatremia3 (2)3 (2)Renal and urinary disordersRenal failure (4)2 (1)Vascular disordersHypotension (7)4 (3)Deep vein thrombosis (4)5 (4)Neoplasms benign, malignant and unspecified (including cysts and polyps)Tumor flare13 (10)0Squamous cell carcinoma of skin (3)4 (3)InvestigationsWeight decreased17 (13)01-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 or more subjects.-MCL trial Serious AEs All treatment-emergent SAEs in or more subjects. Adverse reactions where at least one resulted in 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.The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1% to 10%) in patients treated with lenalidomide monotherapy for mantle cell lymphoma.Cardiac disorder: Cardiac failureEar and labyrinth disorders: VertigoGeneral disorders and administration site conditions: ChillsInfections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes Musculoskeletal and connective tissue disorders: Pain in extremityNervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy Psychiatric disorders: InsomniaSkin and subcutaneous tissue disorders: Dry skin, night sweatsThe following serious adverse reactions not described above and reported in or more patients treated with lenalidomide monotherapy for mantle cell lymphoma.Blood and lymphatic system disorders: NeutropeniaCardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardiaInfections and infestations: Clostridium difficile colitis, sepsisNeoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinomaRespiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism. 6.2 Postmarketing Experience. The following adverse drug reactions have been identified from the worldwide post-marketing experience with lenalidomide capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure [see Warnings and Precautions Section (5.8 to 5.11, and 5.13)]. Endocrine disorders: Hypothyroidism, hyperthyroidismHepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory testsImmune system disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejectionInfections and infestations: Viral reactivation (such as hepatitis virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reactionRespiratory, thoracic and mediastinal disorders: PneumonitisSkin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS).

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of lenalidomide in human milk, the effects of lenalidomide capsules on the breastfed child, or the effects of lenalidomide on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children from lenalidomide capsules, advise women not to breastfeed during treatment with lenalidomide capsules.

BOXED WARNING SECTION.

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGICTOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM. Embryo-Fetal Toxicity Do not use lenalidomide capsules during pregnancy. Lenalidomide, thalidomide analogue, caused limb abnormalities in developmental monkey study. Thalidomide is known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain negative pregnancy tests before starting lenalidomide treatment. Females of reproductive potential must use forms of contraception or continuously abstain from heterosexual sex during and for weeks after lenalidomide capsules treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, lenalidomide capsules are only available through restricted distribution program, the Lenalidomide REMS program (5.2). Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia)Lenalidomide capsules can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have dose delay/reduction during the major study. Thirty-four percent of patients had to have second dose delay/reduction. Grade or 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 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous and Arterial Thromboembolism Lenalidomide capsules have demonstrated significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide capsules and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patients underlying risks [see Warnings and Precautions (5.4)].. WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISMSee full prescribing information for complete boxed warning.EMBRYO-FETAL TOXICITYLenalidomide, thalidomide analogue, caused limb abnormalities in developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception (5.1).Lenalidomide capsules are available only through restricted distribution program, called the Lenalidomide REMS program (5.2, 17).HEMATOLOGIC TOXICITY. Lenalidomide capsules can cause significant neutropenia and thrombocytopenia (5.3).VENOUS AND ARTERIAL THROMBOEMBOLISMSignificantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving lenalidomide capsules with dexamethasone. Anti-thrombotic prophylaxis is recommended (5.4). Lenalidomide, thalidomide analogue, caused limb abnormalities in developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.. Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception (5.1).Lenalidomide capsules are available only through restricted distribution program, called the Lenalidomide REMS program (5.2, 17).HEMATOLOGIC TOXICITY. Lenalidomide capsules can cause significant neutropenia and thrombocytopenia (5.3).VENOUS AND ARTERIAL THROMBOEMBOLISM. Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving lenalidomide capsules with dexamethasone. Anti-thrombotic prophylaxis is recommended (5.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, component of cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF- and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in thorough QT study. At dose two times the maximum recommended dose, lenalidomide did not prolong the QTc interval. The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.. 12.3 Pharmacokinetics. Absorption Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of lenalidomide capsules in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 and hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation. Administration of single 25 mg dose of lenalidomide capsules with high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for lenalidomide capsules, the drug was administered without regard to food intake. Lenalidomide capsules can be administered with or without food. The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.DistributionIn vitro [14C]-lenalidomide binding to plasma proteins is approximately 30%. Lenalidomide is present in semen at hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of lenalidomide 25 mg daily.EliminationThe mean half-life of lenalidomide is hours in healthy subjects and to hours in patients with MM, MDS or MCL.Metabolism Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5-hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation. Excretion Elimination is primarily renal. Following single oral administration of [14C]-lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate. Specific Populations Renal Impairment: Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), subjects with moderate renal impairment (CLcr 30 to 49 mL/min), subjects with severe renal impairment (CLcr 30 mL/min), and patients with end stage renal disease (ESRD) requiring dialysis were administered single 25 mg dose of lenalidomide capsules. Three healthy subjects of similar age with normal renal function (CLcr 80 mL/min) were also administered single 25 mg dose of lenalidomide capsules. As CLcr decreased, half-life increased and drug clearance decreased linearly. Patients with moderate and severe impairment had 3-fold increase in half-life and 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed during 4-hour hemodialysis session.Adjust the starting dose of lenalidomide capsules in patients with renal impairment based on the CLcr value [see Dosage and Administration (2.6)].Hepatic Impairment: Mild hepatic impairment (defined as total bilirubin 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did not influence the disposition of lenalidomide. No pharmacokinetic data is available for patients with moderate to severe hepatic impairment.Other Intrinsic Factors: Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM, MDS or MCL) did not have clinically relevant effect on lenalidomide clearance in adult patients.Drug Interactions Co-administration of single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide capsules (25 mg) after multiple doses of P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the Cmax or AUC of lenalidomide.Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg), with lenalidomide capsules (25 mg) did not significantly alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of temsirolimus).In vitro studies demonstrated that lenalidomide is substrate of P-glycoprotein (P-gp). Lenalidomide is not substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A11/1, UGT1A11/28, and UGT1A128/28.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Multiple Myeloma. Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed MM:A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of lenalidomide and low-dose dexamethasone (Rd) given for different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed MM patients who were not candidate for stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for maximum of twelve 42-day cycles (72 weeks). For the purposes of this study, patient who was 65 years of age was not candidate for SCT if the patient refused to undergo SCT therapy or the patient did not have access to SCT due to cost or other reasons. Patients were stratified at randomization by age (<=75 versus >75 years), stage (ISS Stages and II versus Stage III), and country. Patients in the Rd Continuous and Rd18 arms received lenalidomide 25 mg once daily on Days to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22 of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic anticoagulation with the most commonly used being aspirin. The demographics and disease-related baseline characteristics of the patients were balanced among the arms. In general, study subjects had advanced-stage disease. Of the total study population, the median age was 73 in the arms with 35% of total patients 75 years of age; 59% had ISS Stage I/II; 41% had ISS stage III; 9% had severe renal impairment (creatinine clearance [CLcr] 30 mL/min); 23% had moderate renal impairment (CLcr 30 to 50 mL/min; 44% had mild renal impairment (CLcr 50 to 80 mL/min). For ECOG Performance Status, 29% were Grade 0, 49% Grade 1, 21% Grade 2, 0.4% >= Grade 3. The primary efficacy endpoint, progression-free survival (PFS), was defined as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group [IMWG] criteria or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms. The efficacy results are summarized in the table below. PFS was significantly longer with Rd Continuous than MPT: HR 0.72 (95% CI: 0.61 to 0.85 <0.0001). lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm. For the interim OS analysis with 03 March 2014 data cutoff, the median follow-up time for all surviving patients is 45.5 months, with 697 death events, representing 78% of prespecified events required for the planned final OS analysis (697/896 of the final OS events). The observed OS HR was 0.75 for Rd Continuous versus MPT (95% CI 0.62, 0.90).Table 13: Overview of Efficacy Results Study MM-020 (Intent-to-treat Population)Rd Continuous(N=535)Rd18(N=541)MPT(N=547)PFS IRAC (months)g Number of PFS events 278 (52)348 (64.3)334 (61.1) Mediana PFS time, months (95% CI)b 25.5 (20.7, 29.4)20.7 (19.4, 22)21.2 (19.3, 23.2) HR [95% CI]c; p-valued Rd Continuous vs MPT 0.72 (0.61, 0.85); <0.0001 Rd Continuous vs Rd18 0.70 (0.60, 0.82) Rd18 vs MPT 1.03 (0.89, 1.20)Overall Survival (months)h Number of Death events 208 (38.9)228 (42.1)261 (47.7) Mediana OS time, months (95% CI)b 58.9 (56, NE)f 56.7 (50.1, NE)48.5 (44.2, 52) HR [95% CI]c Rd Continuous vs MPT 0.75 (0.62, 0.90) Rd Continuous vs Rd18 0.91 (0.75, 1.09) Rd18 vs MPT 0.83 (0.69, 0.99)Response Ratee IRAC, (%)g CR 81 (15.1)77 (14.2)51 (9.3) VGPR 152 (28.4)154 (28.5)103 (18.8) PR 169 (31.6)166 (30.7)187 (34.2) Overall response: CR, VGPR, or PR 402 (75.1)397 (73.4)341 (62.3)CR complete response; = low-dose dexamethasone; HR hazard ratio; IRAC Independent Response Adjudication Committee; = melphalan; NE not estimable; OS overall survival; = prednisone; PFS progression-free survival; PR partial response; = lenalidomide; Rd Continuous Rd given until documentation of progressive disease; Rd18 Rd given for <= 18 cycles; = thalidomide; VGPR very good partial response; vs versus. The median is based on the Kaplan-Meier estimate.b The 95% Confidence Interval (CI) about the median. Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms. The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms. Best assessment of response during the treatment phase of the study. Including patients with no response assessment data or whose only assessment was response not evaluable. Data cutoff date 24 May 2013. Data cutoff date 3 March 2014. Kaplan-Meier Curves of Progression-free Survival Based on IRAC Assessment (ITT MM Population) Between Arms Rd Continuous, Rd18 and MPT Cutoff date: 24 May 2013CI confidence interval; = low-dose dexamethasone; HR hazard ratio; IRAC Independent Response Adjudication Committee; = melphalan; = prednisone; = lenalidomide; Rd Continuous Rd given until documentation of progressive disease; Rd18 Rd given for <= 18 cycles; = thalidomide. Kaplan-Meier Curves of Overall Survival (ITT MM Population) Between Arms Rd Continuous, Rd18 and MPT Cutoff date: 03 Mar 2014CI confidence interval; = low-dose dexamethasone; HR hazard ratio; = melphalan; = prednisone; = lenalidomide; Rd Continuous Rd given until documentation of progressive disease; Rd18 Rd given for <=18 cycles; = thalidomide.Randomized, Open-Label Clinical Studies in Patients with MM After At Least One Prior TherapyTwo randomized studies (Studies and 2) were conducted to evaluate the efficacy and safety of lenalidomide. These multicenter, multinational, double-blind, placebo-controlled studies compared lenalidomide plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with MM who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) >= 1000/mm3, platelet counts >= 75,000/mm3, serum creatinine <= 2.5 mg/dL, serum SGOT/AST or SGPT/ALT <= x upper limit of normal (ULN), and serum direct bilirubin <= mg/dL. In both studies, patients in the lenalidomide/dexamethasone group took 25 mg of lenalidomide orally once daily on Days to 21 and matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took placebo capsule on Days to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days to 4, to 12, and 17 to 20 of each 28-day cycle for the first cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on Days to of each 28-day cycle after the first cycles of therapy. In both studies, treatment was to continue until disease progression. In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and mg daily were allowed for toxicity [see Dosage and Administration (2.1)]. Table 16 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the lenalidomide/dexamethasone and placebo/dexamethasone groups.Table 16: Baseline Demographic and Disease-Related Characteristics MM Studies and 2Study 1Study 2Lenalidomide/DexN=177Placebo/DexN=176Lenalidomide/DexN=176Placebo/DexN=175Patient Characteristics Age (years) Median64626364 Min, Max36, 8637, 8533, 8440, 82Sex Male106 (60%)104 (59%)104 (59%)103 (59%) Female71 (40%)72 (41%)72 (41%)72 (41%)Race/Ethnicity White141(80%)148 (84%)172 (98%)175 (100%) Other36 (20%)28 (16%)4 (2%)0 (0%)ECOG Performance Status 0-1 157 (89%)168 (95%)150 (85%)144 (82%)Disease Characteristics Multiple Myeloma Stage (Durie-Salmon)I3%3%6%5%II32%31%28%33%III64%66%65%63%2-microglobulin (mg/L) <= 2.5 mg/L 52 (29%)51 (29%)51 (29%)48 (27%) 2.5 mg/L 125 (71%)125 (71%)125 (71%)127 (73%)Number of Prior Therapies 38%38%32%33% >= 62%62%68%67%Types of Prior Therapies Stem Cell Transplantation 62%61%55%54%Thalidomide 42%46%30%38%Dexamethasone 81%71%66%69%Bortezomib11%11%5%4%Melphalan 33%31%56%52%Doxorubicin 55%51%56%57%The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease. Preplanned interim analyses of both studies showed that the combination of lenalidomide/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the lenalidomide/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95% CI: 32.9, 47.4) in lenalidomide/dexamethasone group and 31.6 months (95% CI: 24.1, 40.9) in placebo/dexamethasone group, with hazard ratio of 0.79 (95% CI: 0.61 to 1.03). In study 2, the median survival time was 37.5 months (95% CI: 29.9, 46.6) in lenalidomide/dexamethasone group and 30.8 months (95% CI: 23.5, 40.3) in placebo/dexamethasone group, with hazard ratio of 0.86 (95% CI: 0.65 to 1.14).Table 17: TTP Results in MM Study and Study 2Study 1Study 2Lenalidomide/DexN=177Placebo/DexN=176Lenalidomide/DexN=176Placebo/Dex N=175TTP Events (%)73 (41)120 (68)68 (39)130 (74)Median TTP in months [95% CI]13.9 [9.5, 18.5]4.7 [3.7, 4.9]12.1 [9.5, NE]4.7 [3.8, 4.8]Hazard Ratio 0.285 0.324 [95% CI][0.210, 0.386][0.240, 0.438]Log-rank Test p-value <0.001<0.001ResponseComplete Response (CR) (%)23 (13)1 (1)27 (15)7 (4)Partial Response (RR/PR) (%)84 (48)33 (19)77 (44)34 (19)Overall Response (%)107 (61)34 (19)104 (59)41 (23)p-value<0.001<0.001Odds Ratio [95% CI]6.38 [3.95, 10.32]4.72 [2.98, 7.49]Kaplan-Meier Estimate of Time to Progression -- MM Study 1Kaplan-Meier Estimate of Time to Progression -- MM Study 2. 1. 1. 1. 1. 14.2 Myelodysplastic Syndromes (MDS) with aDeletion 5q Cytogenetic Abnormality. The efficacy and safety of lenalidomide capsules were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1-risk MDS with 5q (q31 to 33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the dosing regimens. Sequential dose reductions to mg daily and mg every other day, as well as dose delays, were allowed for toxicity [see Dosage and Administration (2.2)]. This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received >= units of RBCs within weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) >= 500/mm3, platelet counts >= 50,000/mm3, serum creatinine <= 2.5 mg/dL, serum SGOT/AST or SGPT/ALT <= x upper limit of normal (ULN), and serum direct bilirubin <= mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 18.Table 18: Baseline Demographic and Disease-Related Characteristics in the MDS StudyOverall(N=148)Age (years)Median 71Min, Max 37, 95Gender n(%)Male 51(34.5)Female 97(65.5)Race n(%)White 143(96.6)Other 5(3.4)Duration of MDS (years)Median2.5Min, Max0.1, 20.7Del (q31-33) Cytogenetic Abnormalityn(%)Yes148(100)Other cytogenetic abnormalities37(25.2)IPSS Score n(%)Low (0)55(37.2)Intermediate-1 (0.5 to 1.0)65(43.9)Intermediate-2 (1.5 to 2.0)6(4.1)High (>=2.5)2(1.4)Missing 20(13.5)FAB Classification from central reviewn(%)RA77(52)RARS16(10.8)RAEB30(20.3)CMML3(2)a IPSS Risk Category: Low (combined score 0), Intermediate-1 (combined score 0.5 to 1), Intermediate-2 (combined score 1.5 to 2.0), High (combined score >= 2.5); Combined score (Marrow blast score Karyotype score Cytopenia score).b French-American-British (FAB) classification of MDS.The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive rolling 56 days (8 weeks) during the treatment period. Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of to >67 weeks). Ninety percent of patients who achieved transfusion benefit did so by completion of three months in the study. RBC transfusion independence rates were unaffected by age or gender. The dose of lenalidomide capsules was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, to 253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, to 265 days). second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15 to 205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, to 148 days). 14.3 Mantle Cell Lymphoma. multicenter, single-arm, open-label trial of single-agent lenalidomide was conducted to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or bortezomib-containing regimen. Patients with creatinine clearance >=60 mL/min were given lenalidomide at dose of 25 mg once daily for 21 days every 28 days. Patients with creatinine clearance >=30 mL/min and <60 mL/min were given lenalidomide at dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) >=1500/mm3, platelet counts >= 60,000/mm3, serum SGOT/AST or SGPT/ALT <=3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin <=1.5 ULN except in cases of Gilberts syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) >=30 mL/min.The median age was 67 years (43 to 83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.Table 19: Baseline Disease-related Characteristics and Prior Anti-Lymphoma Therapy in Mantle Cell Lymphoma TrialBaseline Disease Characteristics and Prior Anti-Lymphoma TreatmentTotal Patients(N=134)ECOG Performance Statusa (%) 043 (32) 173 (54) 217 (13) 31 (<1)Advanced MCL Stage, (%) III27 (20) IV97 (72)High or Intermediate MIPI Score b, (%)90 (67)High Tumor Burdenc, (%)77 (57)Bulky Diseased, (%)44 (33)Extranodal Disease, (%)101 (75)Number of Prior Systemic Anti-Lymphoma Therapies, (%) Median (range)4 (2, 10) 10 (0) 229 (22) 334 (25) >= 471 (53)Number of Subjects Who Received Prior Regimen Containing, (%): Anthracycline/mitoxantrone133 (99) Cyclophosphamide133 (99) Rituximab134 (100) Bortezomib134 (100)Refractory to Prior Bortezomib, (%)81 (60)Refractory to Last Prior Therapy, (%)74 (55)Prior Autologous Bone Marrow or Stem Cell Transplant, (%)39 (29)a ECOG Eastern Cooperative Oncology Group.b MIPI MCL International Prognostic Index.c High tumor burden is defined as at least one lesion that is >=5 cm in diameter or lesions that are >=3 cm in diameter.d Bulky disease is defined as at least one lesion that is >=7 cm in the longest diameter.The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 20. The median time to response was 2.2 months (range 1.8 to 13 months).Table 20: Response Outcomes in the Pivotal Mantle Cell Lymphoma TrialResponse Analyses (N 133) (%)95% CIOverall Response Rate (IWRC) (CR CRu +PR)34 (26)(18.4, 33.9)Complete Response (CR CRu)9 (7)(3.1, 12.5) CR1 (1) CRu8 (6)Partial Response (PR)25 (19)Duration of Response (months)Median95% CIDuration of Overall Response (CR CRu PR) (N 34)16.6(7.7, 26.7).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Pregnancy (Boxed Warning, 4.1, 5.1, 8.1).Demonstrated severe hypersensitivity to lenalidomide (4.2, 5.9, 5.15).. Pregnancy (Boxed Warning, 4.1, 5.1, 8.1).. Demonstrated severe hypersensitivity to lenalidomide (4.2, 5.9, 5.15).. 4.1 Pregnancy. Lenalidomide capsules can cause fetal harm when administered to 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 lenalidomides structural similarities to thalidomide, 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 fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1, 8.3)]. 4.2 Severe Hypersensitivity Reactions. Lenalidomide capsules are 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)].

DESCRIPTION SECTION.

11 DESCRIPTION. Lenalidomide, thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dioneThe empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.Lenalidomide is cream to light yellow color powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as racemic mixture with net optical rotation of zero. Lenalidomide is available in mg, 10 mg, 15 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: anhydrous lactose. The capsule shell ingredients common to all strengths are gelatin and titanium dioxide. Each capsule is printed with black ink, which includes black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution.. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. MM combination therapy: 25 mg once daily orally on Days to 21 of repeated 28-day cycles. (2.1).MDS: 10 mg once daily (2.2). MCL: 25 mg once daily orally on Days to 21 of repeated 28-day cycles (2.3).Renal impairment: Adjust starting dose based on the creatinine clearance value (2.6).For concomitant therapy doses, see Full Prescribing Information (2.1, 14.1).. MM combination therapy: 25 mg once daily orally on Days to 21 of repeated 28-day cycles. (2.1).. MDS: 10 mg once daily (2.2). MCL: 25 mg once daily orally on Days to 21 of repeated 28-day cycles (2.3).. Renal impairment: Adjust starting dose based on the creatinine clearance value (2.6).. For concomitant therapy doses, see Full Prescribing Information (2.1, 14.1).. 2.1 Recommended Dosage for Multiple Myeloma. Lenalidomide Capsules Combination TherapyThe recommended starting dose of lenalidomide capsules is 25 mg orally once daily on Days to 21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced [see Clinical Studies (14.1)]. Treatment should be continued until disease progression or unacceptable toxicity.In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within cycles of lenalidomide-containing therapy [see Warnings and Precautions (5.12)].Dose Adjustments for Hematologic Toxicities During MM Treatment Dose modification guidelines, as summarized in Table below, are recommended to manage Grade or neutropenia or thrombocytopenia or other Grade or toxicity judged to be related to lenalidomide capsules.Table 1: Dose Adjustments for Hematologic Toxicities for MMPlatelet counts Thrombocytopenia in MM When PlateletsRecommended CourseDays to 21 of repeated 28-day cycle Fall below 30,000/mcLInterrupt lenalidomide capsules treatment, follow CBC weekly Return to at least 30,000/mcLResume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily For each subsequent drop below 30,000/mcLInterrupt lenalidomide capsules treatment Return to at least 30,000/mcLResume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg dailyAbsolute Neutrophil counts (ANC) Neutropenia in MM When NeutrophilsRecommended CourseDays to 21 of repeated 28-day cycle Fall below 1000/mcLInterrupt lenalidomide capsules treatment, follow CBC weekly Return to at least 1,000/mcL and neutropenia is the only toxicity Resume lenalidomide capsules at 25 mg daily or initial starting dose Return to at least 1,000/mcL and if other toxicity Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily For each subsequent drop below 1,000/mcLInterrupt lenalidomide capsules treatment Return to at least 1,000/mcLResume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily. 2.2 Recommended Dosage for MyelodysplasticSyndromes. The recommended starting dose of lenalidomide capsules is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.Dose Adjustments for Hematologic Toxicities During MDS TreatmentPatients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows: Platelet counts If thrombocytopenia develops WITHIN weeks of starting treatment at 10 mg daily in MDSIf baseline is at least 100,000/mcLWhen PlateletsRecommended CourseFall below 50,000/mcLInterrupt lenalidomide capsules treatment Return to at least 50,000/mcLResume lenalidomide capsules at mg dailyIf baseline is below 100,000/mcLWhen PlateletsRecommended CourseFall to 50% of the baseline valueInterrupt lenalidomide capsules treatmentIf baseline is at least 60,000/mcL and returns to at least 50,000/mcLResume lenalidomide capsules at mg dailyIf baseline is below 60,000/mcL and returns to at least 30,000/mcLResume lenalidomide capsules at mg dailyIf thrombocytopenia develops AFTER weeks of starting treatment at 10 mg daily in MDSWhen PlateletsRecommended CourseFall below 30,000/mcL or below 50,000/mcL with platelet transfusionsInterrupt lenalidomide capsules treatment Return to at least 30,000/mcL (without hemostatic failure)Resume lenalidomide capsules at mg dailyPatients who experience thrombocytopenia at mg daily should have their dosage adjusted as follows:If thrombocytopenia develops during treatment at mg daily in MDSWhen PlateletsRecommended CourseFall below 30,000/mcL or below 50,000/mcL with platelet transfusionsInterrupt lenalidomide capsules treatment Return to at least 30,000/mcL (without hemostatic failure)Resume lenalidomide capsules at 2.5 mg dailyPatients 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 weeks of starting treatment at 10 mg daily in MDSIf baseline ANC is at least 1,000/mcLWhen NeutrophilsRecommended CourseFall below 750/mcLInterrupt lenalidomide capsules treatment Return to at least 1,000/mcLResume lenalidomide capsules at mg dailyIf baseline ANC is below 1,000/mcLWhen NeutrophilsRecommended CourseFall below 500/mcLInterrupt lenalidomide capsules treatmentReturn to at least 500/mcLResume lenalidomide capsules at mg dailyIf neutropenia develops AFTER weeks of starting treatment at 10 mg daily in MDSWhen NeutrophilsRecommended CourseFall below 500/mcL for at least days or below 500/mcL associated with fever (at least 38.5C) Interrupt lenalidomide capsules treatment Return to at least 500/mcLResume lenalidomide capsules at mg dailyPatients who experience neutropenia at mg daily should have their dosage adjusted as follows:If neutropenia develops during treatment at mg daily in MDSWhen NeutrophilsRecommended CourseFall below 500/mcL for at least days or below 500/mcL associated with fever (at least 38.5oC) Interrupt lenalidomide capsules treatment Return to at least 500/mcLResume lenalidomide capsules at 2.5 mg daily. 2.3 Recommended Dosage for Mantle Cell Lymphoma. The recommended starting dose of lenalidomide capsules is 25 mg/day orally on Days to 21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity.Treatment is continued, modified or discontinued based upon clinical and laboratory findings.Dose Adjustments for Hematologic Toxicities During MCL TreatmentDose modification guidelines as summarized below are recommended to manage Grade or neutropenia or thrombocytopenia or other Grade or toxicities considered to be related to lenalidomide capsules.Platelet countsThrombocytopenia during treatment in MCLWhen Platelets Recommended CourseFall below 50,000/mcL Interrupt lenalidomide capsules treatment and follow CBC weeklyReturn to at least 50,000/mcL Resume lenalidomide capsules at mg less than the previous dose. Do not dose below mg dailyAbsolute Neutrophil counts (ANC)Neutropenia during treatment in MCLWhen Neutrophils Recommended CourseFall below 1000/mcL for at least daysORFalls below 1,000/mcL with an associated temperature at least 38.5CORFalls below 500/mcLInterrupt lenalidomide capsules treatment and follow CBC weeklyReturn to at least 1,000/mcL Resume lenalidomide capsules at mg less than the previous dose. Do not dose below mg daily. 2.5 Dosage Modifications for Non-HematologicAdverse Reactions. For non-hematologic Grade 3/4 toxicities judged to be related to lenalidomide capsules, hold treatment and restart at the physicians discretion at next lower dose level when toxicity has resolved to Grade or below.Permanently discontinue lenalidomide capsules for angioedema, anaphylaxis, Grade rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.9, 5.15)].. 2.6 Recommended Dosage for Patients with RenalImpairment. The recommendations for dosing patients with renal impairment are shown in the following table [see Clinical Pharmacology (12.3)].Table 3: Dose Adjustments for Patients with Renal ImpairmentRenal Function(Cockcroft-Gault)Dose in Lenalidomide Capsules Combination Therapy for MM and MCLDose in Lenalidomide Capsules for MDSCLcr 30 to 60 mL/min10 mg once daily5 mg once daily CLcr below 30 mL/min (not requiring dialysis) 15 mg every other day2.5 mg once daily CLcr below 30 mL/min (requiring dialysis) mg once daily. On dialysis days, administer the dose following dialysis.2.5 mg once daily. On dialysis days, administer the dose following dialysis. Lenalidomide Capsules Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.Lenalidomide Capsules Therapy for MCL and MDS: Base subsequent lenalidomide capsules dose increase or decrease on individual patient treatment tolerance [see Dosage and Administration (2.1 to 2.3)]. 2.7 Administration. Advise patients to take lenalidomide capsules orally at about the same time each day, either with or without food. Advise patients to swallow lenalidomide capsules whole with water and not to open, break, or chew them.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules:5 mg white capsules printed with NAT on cap and 5mg on body of the capsule in black ink.10 mg white capsules printed with NAT on cap and 10mg on body of the capsule in black ink.15 mg white capsules printed with NAT on cap and 15mg on body of the capsule in black ink.25 mg white capsules printed with NAT on cap and 25mg on body of the capsule in black ink.. mg white capsules printed with NAT on cap and 5mg on body of the capsule in black ink.. 10 mg white capsules printed with NAT on cap and 10mg on body of the capsule in black ink.. 15 mg white capsules printed with NAT on cap and 15mg on body of the capsule in black ink.. 25 mg white capsules printed with NAT on cap and 25mg on body of the capsule in black ink.. Capsules: mg, 10 mg, 15 mg, and 25 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Digoxin: Monitor digoxin plasma levels periodically due to increased Cmax and AUC with concomitant lenalidomide capsules therapy (7.1). Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with lenalidomide capsules may increase the risk of thrombosis (7.2). Digoxin: Monitor digoxin plasma levels periodically due to increased Cmax and AUC with concomitant lenalidomide capsules therapy (7.1). Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with lenalidomide capsules may increase the risk of thrombosis (7.2). 7.1 Digoxin. When digoxin was co-administered with multiple doses of lenalidomide capsules (10 mg/day) the digoxin Cmax and AUCinf 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 lenalidomide capsules. 7.2 Concomitant Therapies That May Increase theRisk 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 benefit-risk assessment in patients receiving lenalidomide [see Warnings and Precautions (5.4)]. 7.3 Warfarin. Co-administration of multiple doses of lenalidomide capsules (10 mg/day) with 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 lenalidomide capsules 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingLenalidomide capsules can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating lenalidomide capsules therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy weeks before therapy, while taking lenalidomide capsules, during dose interruptions and for at least weeks after completing therapy. Females of reproductive potential must have negative pregnancy tests before initiating lenalidomide capsules. The first test should be performed within 10 to 14 days, and the second test within 24 hours prior to prescribing lenalidomide capsules. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first weeks of use, then pregnancy testing should be repeated every weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every weeks. Pregnancy testing and counseling should be performed if patient misses her period or if there is any abnormality in her menstrual bleeding. Lenalidomide treatment must be discontinued during this evaluation. ContraceptionFemalesFemales of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use methods of reliable birth control simultaneously: one highly effective form of contraception tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partners vasectomy, and additional effective contraceptive method male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin weeks prior to initiating treatment with lenalidomide capsules, during therapy, during dose interruptions, and continuing for weeks following discontinuation of lenalidomide therapy. Reliable contraception is indicated even where there has been history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to qualified provider of contraceptive methods, if needed. Males Lenalidomide is present in the semen of males who take lenalidomide capsules. Therefore, males must always use latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to weeks after discontinuing lenalidomide capsules, even if they have undergone successful vasectomy. Male patients taking lenalidomide capsules must not donate sperm.

GERIATRIC USE SECTION.

8.5 Geriatric Use. MM In Combination: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521/1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the adverse reaction categories (eg, all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was higher in older (> 75 years of age) than in younger (<= 75 years of age) subjects. Grade or adverse reactions in the General Disorders and Administration Site Conditions body system were consistently reported at higher frequency (with difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade or adverse reactions in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other body systems (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger subjects across all treatment arms Serious adverse reactions were generally reported at higher frequency in the older subjects than in the younger subjects across all treatment arms.MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received lenalidomide/dexamethasone, 46% were age 65 and over. In both studies, patients 65 years of age were more likely than patients <= 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide capsules. No differences in efficacy were observed between patients over 65 years of age and younger patients. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%). greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse reactions was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade and adverse reactions was also similar in these patient groups (79% vs. 78%, respectively). The frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Lenalidomide capsules are available as follows:5 mg Each size capsule with white cap and body printed with NAT on cap and 5mg on body in black ink contains mg of lenalidomide. mg bottles of 28 (NDC 0480-1242-28)10 mg Each size capsule with white cap and body printed with NAT on cap and 10mg on body in black ink contains 10 mg of lenalidomide. 10 mg bottles of 28 (NDC 0480-1243-28)15 mg Each size capsule with white cap and body printed with NAT on cap and 15mg on body in black ink contains 15 mg of lenalidomide. 15 mg bottles of 21 (NDC 0480-1244-21)25 mg Each size capsule with white cap and body printed with NAT on cap and 25mg on body in black ink contains 25 mg of lenalidomide. 25 mg bottles of 21 (NDC 0480-1246-21). 16.2 Storage. Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. 16.3 Handling and Disposal. Care should be exercised in the handling of lenalidomide capsules. Lenalidomide capsules should not be opened or broken. If powder from lenalidomide capsules contacts the skin, wash the skin immediately and thoroughly with soap and water. If lenalidomide contacts the mucous membranes, flush thoroughly with water.Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1 Dispense no more than 28-day supply.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Lenalidomide is thalidomide analogue indicated for the treatment of adult patients with: Multiple myeloma (MM), in combination with dexamethasone (1.1). Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities (1.2). Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (1.3).Limitations of Use:Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials (1.6). Multiple myeloma (MM), in combination with dexamethasone (1.1). Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities (1.2). Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (1.3).. Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials (1.6). 1.1 Multiple Myeloma. Lenalidomide capsules in combination with dexamethasone are indicated for the treatment of adult patients with multiple myeloma (MM).. 1.2 Myelodysplastic Syndromes. Lenalidomide capsules are indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 1.3 Mantle Cell Lymphoma. Lenalidomide capsules are indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.. 1.6 Limitations of Use. Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved Patient labeling (Medication Guide) Embryo-Fetal ToxicityAdvise patients that lenalidomide capsules are contraindicated in pregnancy [see Boxed Warning and Contraindications (4.1)]. Lenalidomide is thalidomide analogue and can cause serious birth defects or death to developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Advise females of reproductive potential that they must avoid pregnancy while taking lenalidomide capsules and for at least weeks after completing therapy. Initiate lenalidomide capsules treatment in females of reproductive potential only following negative pregnancy test. Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use different forms of contraception including at least highly effective form, simultaneously during lenalidomide capsules therapy, during dose interruption and for weeks after she has completely finished taking lenalidomide capsules. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and partners vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. Instruct patient to immediately stop taking lenalidomide capsules and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. Advise patient that if her healthcare provider is not available, she should call Customer Care Center at 1-888-423-5436 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. Advise males to always use latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to weeks after discontinuing lenalidomide capsules, even if they have undergone successful vasectomy. Advise male patients taking lenalidomide capsules that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. All patients must be instructed to not donate blood while taking lenalidomide capsules, during dose interruptions and for weeks following discontinuation of lenalidomide capsules [see Warnings and Precautions (5.1)]. Lenalidomide REMS program Because of the risk of embryo-fetal toxicity, lenalidomide capsules are only available through restricted program called the Lenalidomide REMS program [see Warnings and Precautions (5.2)].Patients must sign Patient-Physician agreement form and comply with the requirements to receive lenalidomide capsules. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.3)]. Lenalidomide capsules are available only from pharmacies that are certified in Lenalidomide REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Pregnancy Exposure RegistryInform females there is Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to lenalidomide capsules during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436 [see Use in Specific Populations (8.1)].Hematologic Toxicity Inform patients that lenalidomide capsules are associated with significant neutropenia and thrombocytopenia [see Boxed Warning and Warnings and Precautions (5.3)]. Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warning and Warnings and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that lenalidomide capsules had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warnings and Precautions (5.5)]. Second Primary MalignanciesInform patients of the potential risk of developing second primary malignancies during treatment with lenalidomide capsules [see Warnings and Precautions (5.6)].Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.8)].Severe Cutaneous Reactions Inform patients of the potential risk for severe skin reactions such as SJS, TEN, and DRESS and report any signs and symptoms associated with these reactions to their healthcare provider for evaluation. Patients with prior history of Grade rash associated with thalidomide treatment should not receive lenalidomide capsules [see Warnings and Precautions (5.9)].Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)].Tumor Flare ReactionInform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.11)].Early Mortality in Patients with MCLInform patients with MCL of the potential for early death [see Warnings and Precautions (5.14)].HypersensitivityInform patients of the potential for severe hypersensitivity reactions such as angioedema and anaphylaxis to lenalidomide capsules. Instruct patients to contact their healthcare provider right away for signs and symptoms of these reactions. Advise patients to seek emergency medical attention for signs or symptoms of severe hypersensitivity reactions [see Warnings and Precautions (5.15)].Dosing Instructions Inform patients how to take lenalidomide capsules [see Dosage and Administration (2)] Lenalidomide capsules should be taken once daily at about the same time each day, Lenalidomide capsules may be taken either with or without food. The capsules should not be opened, broken, or chewed. Lenalidomide capsules should be swallowed whole with water.Instruct patients that if they miss dose of lenalidomide capsules, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take lenalidomide capsules at the usual time. Warn patients to not take doses to make up for the one that they missed. Manufactured In India By: Natco Pharma Limited Kothur 509 228, IndiaORManufactured In India By: Natco Pharma Limited Visakhapatnam 531019, AP, IndiaManufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Iss. 9/2021 Advise females of reproductive potential that they must avoid pregnancy while taking lenalidomide capsules and for at least weeks after completing therapy. Initiate lenalidomide capsules treatment in females of reproductive potential only following negative pregnancy test. Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use different forms of contraception including at least highly effective form, simultaneously during lenalidomide capsules therapy, during dose interruption and for weeks after she has completely finished taking lenalidomide capsules. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and partners vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. Instruct patient to immediately stop taking lenalidomide capsules and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. Advise patient that if her healthcare provider is not available, she should call Customer Care Center at 1-888-423-5436 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. Advise males to always use latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to weeks after discontinuing lenalidomide capsules, even if they have undergone successful vasectomy. Advise male patients taking lenalidomide capsules that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. All patients must be instructed to not donate blood while taking lenalidomide capsules, during dose interruptions and for weeks following discontinuation of lenalidomide capsules [see Warnings and Precautions (5.1)]. Patients must sign Patient-Physician agreement form and comply with the requirements to receive lenalidomide capsules. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.3)]. Lenalidomide capsules are available only from pharmacies that are certified in Lenalidomide REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Lenalidomide capsules should be taken once daily at about the same time each day, Lenalidomide capsules may be taken either with or without food. The capsules should not be opened, broken, or chewed. Lenalidomide capsules should be swallowed whole with water.. Instruct patients that if they miss dose of lenalidomide capsules, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take lenalidomide capsules at the usual time. Warn patients to not take doses to make up for the one that they missed.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, component of cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF- and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. NDC 0480-1242-28 Rx onlyLenalidomide Capsules5 mgWARNING: POTENTIAL FOR HUMAN BIRTH DEFECTSPHARMACIST: Dispense the accompanying Medication Guide to each patient.28 Capsules. 1.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in thorough QT study. At dose two times the maximum recommended dose, lenalidomide did not prolong the QTc interval. The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of lenalidomide capsules in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 and hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation. Administration of single 25 mg dose of lenalidomide capsules with high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for lenalidomide capsules, the drug was administered without regard to food intake. Lenalidomide capsules can be administered with or without food. The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.DistributionIn vitro [14C]-lenalidomide binding to plasma proteins is approximately 30%. Lenalidomide is present in semen at hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of lenalidomide 25 mg daily.EliminationThe mean half-life of lenalidomide is hours in healthy subjects and to hours in patients with MM, MDS or MCL.Metabolism Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5-hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation. Excretion Elimination is primarily renal. Following single oral administration of [14C]-lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate. Specific Populations Renal Impairment: Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), subjects with moderate renal impairment (CLcr 30 to 49 mL/min), subjects with severe renal impairment (CLcr 30 mL/min), and patients with end stage renal disease (ESRD) requiring dialysis were administered single 25 mg dose of lenalidomide capsules. Three healthy subjects of similar age with normal renal function (CLcr 80 mL/min) were also administered single 25 mg dose of lenalidomide capsules. As CLcr decreased, half-life increased and drug clearance decreased linearly. Patients with moderate and severe impairment had 3-fold increase in half-life and 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed during 4-hour hemodialysis session.Adjust the starting dose of lenalidomide capsules in patients with renal impairment based on the CLcr value [see Dosage and Administration (2.6)].Hepatic Impairment: Mild hepatic impairment (defined as total bilirubin 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did not influence the disposition of lenalidomide. No pharmacokinetic data is available for patients with moderate to severe hepatic impairment.Other Intrinsic Factors: Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM, MDS or MCL) did not have clinically relevant effect on lenalidomide clearance in adult patients.Drug Interactions Co-administration of single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide capsules (25 mg) after multiple doses of P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the Cmax or AUC of lenalidomide.Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg), with lenalidomide capsules (25 mg) did not significantly alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of temsirolimus).In vitro studies demonstrated that lenalidomide is substrate of P-glycoprotein (P-gp). Lenalidomide is not substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A11/1, UGT1A11/28, and UGT1A128/28.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lenalidomide capsules during pregnancy as well as female partners of male patients who are exposed to lenalidomide capsules. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to lenalidomide capsules to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the Lenalidomide REMS program at 1-888-423-5436.Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies [see Data], lenalidomide can cause embryo-fetal harm when administered to pregnant female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4.1), and Use in Specific Populations (5.1)].Lenalidomide is thalidomide analogue. Thalidomide is human teratogen, inducing 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 [see Data]. 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 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 lenalidomide capsules to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the Lenalidomide REMS program at 1-888-423-5436.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.DataAnimal dataIn 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 pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed 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 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20% to 40% of the maternal Cmax. Following 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.1, 5.2) 8/2021.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] OSHA Hazardous Drugs. OSHA [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html].

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. Adjust the starting dose of lenalidomide capsules based on the creatinine clearance value and for patients on dialysis [see Dosage and Administration (2.6)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. LENALIDOMIDE (len lid oh mide) Capsules What is the most important information should know about lenalidomide capsules Before you begin taking lenalidomide capsules, you must read and agree to all of the instructions in the Lenalidomide REMS program. Before prescribing lenalidomide capsules, your healthcare provider will explain the Lenalidomide REMS program to you and have you sign the Patient-Physician Agreement Form. Lenalidomide capsules may cause serious side effects including: Possible birth defects (deformed babies) or death of an unborn baby. Females who are pregnant or who plan to become pregnant must not take lenalidomide capsules. Lenalidomide is similar to the medicine thalidomide. We know thalidomide can cause severe life-threatening birth defects. Lenalidomide capsules have not been tested in pregnant females. Lenalidomide capsules have harmed unborn animals in animal testing. Females must not get pregnant: For at least weeks before starting lenalidomide capsulesWhile taking lenalidomide capsulesDuring any breaks (interruptions) in your treatment with lenalidomide capsulesFor at least weeks after stopping lenalidomide capsules Females who can become pregnant: Will have pregnancy tests weekly for weeks, then every weeks if your menstrual cycle is regular, or every weeks if your menstrual cycle is irregular.If you miss your period or have unusual bleeding, you will need to have pregnancy test and receive counseling.Must agree to use two acceptable forms of birth control at the same time, for at least weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least weeks after stopping lenalidomide capsules.Talk with your healthcare provider to find out about options for acceptable forms of birth control that you may use to prevent pregnancy before, during, and after treatment with lenalidomide capsules.If you had unprotected sex or if you think your birth control has failed, stop taking lenalidomide capsules immediately and call your healthcare provider right away. If you become pregnant while taking lenalidomide capsules, stop taking it right away and call your healthcare provider. If your healthcare provider is not available, you can call Customer Care Center at 1-888-423-5436. Healthcare providers and patients should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088, and The Lenalidomide REMS program at 1-888-423-5436 There is pregnancy exposure registry that monitors the outcomes of females who take lenalidomide capsules during pregnancy, or if their male partner takes lenalidomide capsules and they are exposed during pregnancy. You can enroll in this registry by calling the Lenalidomide REMS program at the phone number listed above. Lenalidomide can pass into human semen: Males, including those who have had vasectomy, must always use latex or synthetic condom during any sexual contact with pregnant female or female that can become pregnant while taking lenalidomide capsules, during any breaks (interruptions) in your treatment with lenalidomide capsules, and for up to weeks after stopping lenalidomide capsules. Do not have unprotected sexual contact with female who is or could become pregnant. Tell your healthcare provider if you do have unprotected sexual contact with female who is or could become pregnant. Do not donate sperm while taking lenalidomide capsules, during any breaks (interruptions) in your treatment, and for weeks after stopping lenalidomide capsules. If female becomes pregnant with your sperm, the baby may be exposed to lenalidomide and may be born with birth defects. Men, if your female partner becomes pregnant, you should call your healthcare provider right away. Low white blood cells (neutropenia) and low platelets (thrombocytopenia). Lenalidomide capsules cause low white blood cells and low platelets in most people. You may need blood transfusion or certain medicines if your blood counts drop too low. Your healthcare provider should check your blood counts often especially during the first several months of treatment with lenalidomide capsules, and then at least monthly. Tell your healthcare provider if you develop any bleeding or bruising, during treatment with lenalidomide capsules.Blood clots. Blood clots in the arteries, veins, and lungs happen more often in people who take lenalidomide capsules. This risk is even higher for people with multiple myeloma who take the medicine dexamethasone with lenalidomide capsules. Heart attacks and strokes also happen more often in people who take lenalidomide capsules with dexamethasone. To reduce this increased risk, most people who take lenalidomide capsules will also take blood thinner medicine. Before taking lenalidomide capsules, tell your healthcare provider: If you have had blood clot in the pastIf you have high blood pressure, smoke, or if you have been told you have high level of fat in your blood (hyperlipidemia)About all the medicines you take. Certain other medicines can also increase your risk for blood clots Call your healthcare provider or get medical help right away if you get any of the following during treatment with lenalidomide capsules:Signs or symptoms of blood clot in the lung, arm, or leg may include: shortness of breath, chest pain, or arm or leg swellingSigns or symptoms of heart attack may include: chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath, feeling sick or vomitingSigns or symptoms of stroke may include: sudden numbness or weakness, especially on one side of the body, severe headache or confusion, or problems with vision, speech, or balance What are lenalidomide capsules Lenalidomide capsules are prescription medicine, used to treat adults with: multiple myeloma (MM)in combination with the medicine dexamethasone condition called myelodysplastic syndromes (MDS). Lenalidomide capsules are for the type of MDS with chromosome problem where part of chromosome is missing. This type of MDS is known as deletion 5q MDS. People with this type of MDS may have low red blood cell counts that require treatment with blood transfusions. mantle cell lymphoma (MCL) when the disease comes back or becomes worse after treatment with prior medicines, one of which included bortezomib. MCL is cancer of type of white blood cell called lymphocytes that are in the lymph nodes.Lenalidomide capsules should not be used to treat people who have chronic lymphocytic leukemia (CLL) unless they are participants in controlled clinical trial. It is not known if lenalidomide capsules are safe and effective in children.Who should not take lenalidomide capsules Do not take lenalidomide capsules if you:are pregnant, plan to become pregnant, or become pregnant during treatment with lenalidomide capsules. See What is the most important information should know about lenalidomide capsules are allergic to lenalidomide or any of the ingredients in lenalidomide capsules. See the end of this Medication Guide for complete list of ingredients in lenalidomide capsules.What should tell my healthcare provider before taking lenalidomide capsules Before you take lenalidomide capsules, tell your healthcare provider about all of your medical conditions, including if you: have liver problemshave kidney problems or receive kidney dialysis treatment have thyroid problemshave had serious skin rash with thalidomide treatment. You should not take lenalidomide capsules.are lactose intolerant. Lenalidomide capsules contain lactose. are breastfeeding. Do not breastfeed during treatment with lenalidomide capsules. It is not known if lenalidomide passes into your breast milk and can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Lenalidomide capsules and other medicines may affect each other, causing serious side effects. Talk with your healthcare provider before taking any new medicines. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist.How should take lenalidomide capsules Take lenalidomide capsules exactly as prescribed and follow all the instructions of the Lenalidomide REMS program Swallow lenalidomide capsules whole with water time day. Do not open, break, or chew your capsules. Lenalidomide capsules may be taken with or without food. Take lenalidomide capsules at about the same time each day. Do not open or break lenalidomide capsules or handle them any more than needed. If powder from the lenalidomide capsule comes in contact with your skin, wash the skin right away with soap and water.If powder from the lenalidomide capsule comes in contact with the inside of your eyes, nose, or mouth, flush well with water. If you miss dose of lenalidomide capsules and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take doses at the same time.If you take too much lenalidomide, call your healthcare provider right away.What should avoid while taking lenalidomide capsules See What is the most important information should know about lenalidomide capsules Females: Do not get pregnant and do not breastfeed while taking lenalidomide capsules. Males: Do not donate sperm. Do not share lenalidomide capsules with other people. It may cause birth defects and other serious problems.Do not donate blood while you take lenalidomide capsules, during any breaks (interruptions) in your treatment, and for weeks after stopping lenalidomide capsules. If someone who is pregnant gets your donated blood, her baby may be exposed to lenalidomide and may be born with birth defects.What are the possible side effects of lenalidomide capsules Lenalidomide capsules can cause serious side effects, including:See What is the most important information should know about lenalidomide capsules Increased risk of death in people who have chronic lymphocytic leukemia (CLL). People with CLL who take lenalidomide capsules have an increased risk of death compared with people who take the medicine chlorambucil. Lenalidomide capsules may cause you to have serious heart problems that can lead to death, including atrial fibrillation, heart attack, or heart failure. You should not take lenalidomide capsules if you have CLL unless you are participating in controlled clinical trial. Risk of new cancers (malignancies). An increase in new (second) cancers has happened in patients who received lenalidomide capsules and melphalan, or blood stem cell transplant, including certain blood cancers, such as acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS) and certain other types of cancers of the skin and other organs. Talk with your healthcare provider about your risk of developing new cancers if you take lenalidomide capsules. Your healthcare provider will check you for new cancers during your treatment with lenalidomide capsules.Severe liver problems, including liver failure and death. Your healthcare provider should do blood tests to check your liver function during your treatment with lenalidomide capsules. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:yellowing of your skin or the white part of your eyes (jaundice)dark or brown (tea-colored) urinepain on the upper right side of your stomach area (abdomen)bleeding or bruising more easily than normalfeeling very tiredSevere skin reactions and severe allergic reactions can happen with lenalidomide capsules and may cause death.Call your healthcare provider right away if you develop any of the following signs or symptoms during treatment with lenalidomide capsules: red, itchy, skin rash peeling of your skin or blisterssevere itchingfeverGet emergency medical help right away if you develop any of the following signs or symptoms during treatment with lenalidomide capsules:swelling of your lips, mouth, tongue, or throattrouble breathing or swallowingraised red areas on your skin (hives)a very fast heartbeatyou feel dizzy or faintTumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and sometimes death. Your healthcare provider may do blood tests to check you for TLS. Worsening of your tumor (tumor flare reaction). Tell your healthcare provider if you get any of these symptoms of tumor flare reaction while taking lenalidomide capsules: tender swollen lymph nodes, low grade fever, pain, or rash. Your healthcare provider may tell you to decrease your dose, temporarily stop or permanently stop taking lenalidomide capsules if you develop certain serious side effects during treatment with lenalidomide capsules.Thyroid problems. Your healthcare provider may check your thyroid function before you start taking lenalidomide capsules and during treatment with lenalidomide capsules.Risk of Early Death in MCL. In people who have Mantle Cell Lymphoma (MCL), there may be risk of dying sooner (early death) when taking lenalidomide capsules. Talk with your healthcare provider about any concerns and possible risk factors. The most common side effects of lenalidomide capsules include:diarrhearash nauseaconstipationtiredness or weaknessfeveritchingswelling of your arms, hands, legs, feet and skin sleep problems (insomnia) headachemuscle cramps or spasmsshortness of breathcough, sore throat, and other symptoms of coldupper respiratory tract infection or bronchitisinflammation of the stomach and intestine (stomach flu)nose bleedshaking or trembling (tremor)joint achespain in your back or stomach-area (abdomen)These are not all the possible side effects of lenalidomide capsules. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store lenalidomide capsulesStore lenalidomide capsules at room temperature between 68F to 77F (20C to 25C). Return any unused lenalidomide capsules to Teva or your healthcare provider.Keep lenalidomide capsules and all medicines out of the reach of children.General information about the safe and effective use of lenalidomide capsules. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not take lenalidomide capsules for conditions for which they were not prescribed. Do not give lenalidomide capsules to other people, even if they have the same symptoms you have. It may harm them and may cause birth defects. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about lenalidomide capsules that is written for health professionals.What are the ingredients in lenalidomide capsules Active ingredient: lenalidomide Inactive ingredients: anhydrous lactose. The capsule shell ingredients common to all strengths contains gelatin and titanium dioxide. Each capsule is printed with black ink, which includes black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution.Manufactured In India By: Natco Pharma Limited, Kothur 509 228, India ORManufactured In India By: Natco Pharma Limited, Visakhapatnam 531019, AP, IndiaManufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 For more information, call 1-888-838-2872 or go to www.lenalidomiderems.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Iss. 9/2021. Possible birth defects (deformed babies) or death of an unborn baby. Females who are pregnant or who plan to become pregnant must not take lenalidomide capsules. For at least weeks before starting lenalidomide capsules. While taking lenalidomide capsules. During any breaks (interruptions) in your treatment with lenalidomide capsules. For at least weeks after stopping lenalidomide capsules. Will have pregnancy tests weekly for weeks, then every weeks if your menstrual cycle is regular, or every weeks if your menstrual cycle is irregular.. If you miss your period or have unusual bleeding, you will need to have pregnancy test and receive counseling.. Must agree to use two acceptable forms of birth control at the same time, for at least weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least weeks after stopping lenalidomide capsules.. Talk with your healthcare provider to find out about options for acceptable forms of birth control that you may use to prevent pregnancy before, during, and after treatment with lenalidomide capsules.. If you had unprotected sex or if you think your birth control has failed, stop taking lenalidomide capsules immediately and call your healthcare provider right away.. FDA MedWatch at 1-800-FDA-1088, and The Lenalidomide REMS program at 1-888-423-5436. Males, including those who have had vasectomy, must always use latex or synthetic condom during any sexual contact with pregnant female or female that can become pregnant while taking lenalidomide capsules, during any breaks (interruptions) in your treatment with lenalidomide capsules, and for up to weeks after stopping lenalidomide capsules. Do not have unprotected sexual contact with female who is or could become pregnant. Tell your healthcare provider if you do have unprotected sexual contact with female who is or could become pregnant. Do not donate sperm while taking lenalidomide capsules, during any breaks (interruptions) in your treatment, and for weeks after stopping lenalidomide capsules. If female becomes pregnant with your sperm, the baby may be exposed to lenalidomide and may be born with birth defects.. Low white blood cells (neutropenia) and low platelets (thrombocytopenia). Lenalidomide capsules cause low white blood cells and low platelets in most people. You may need blood transfusion or certain medicines if your blood counts drop too low. Your healthcare provider should check your blood counts often especially during the first several months of treatment with lenalidomide capsules, and then at least monthly. Tell your healthcare provider if you develop any bleeding or bruising, during treatment with lenalidomide capsules.. Blood clots. Blood clots in the arteries, veins, and lungs happen more often in people who take lenalidomide capsules. This risk is even higher for people with multiple myeloma who take the medicine dexamethasone with lenalidomide capsules. Heart attacks and strokes also happen more often in people who take lenalidomide capsules with dexamethasone. To reduce this increased risk, most people who take lenalidomide capsules will also take blood thinner medicine.. If you have had blood clot in the past. If you have high blood pressure, smoke, or if you have been told you have high level of fat in your blood (hyperlipidemia). About all the medicines you take. Certain other medicines can also increase your risk for blood clots Call your healthcare provider or get medical help right away if you get any of the following during treatment with lenalidomide capsules:Signs or symptoms of blood clot in the lung, arm, or leg may include: shortness of breath, chest pain, or arm or leg swellingSigns or symptoms of heart attack may include: chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath, feeling sick or vomitingSigns or symptoms of stroke may include: sudden numbness or weakness, especially on one side of the body, severe headache or confusion, or problems with vision, speech, or balance Signs or symptoms of blood clot in the lung, arm, or leg may include: shortness of breath, chest pain, or arm or leg swelling. Signs or symptoms of heart attack may include: chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath, feeling sick or vomiting. Signs or symptoms of stroke may include: sudden numbness or weakness, especially on one side of the body, severe headache or confusion, or problems with vision, speech, or balance. multiple myeloma (MM)in combination with the medicine dexamethasone in combination with the medicine dexamethasone. condition called myelodysplastic syndromes (MDS). Lenalidomide capsules are for the type of MDS with chromosome problem where part of chromosome is missing. This type of MDS is known as deletion 5q MDS. People with this type of MDS may have low red blood cell counts that require treatment with blood transfusions. mantle cell lymphoma (MCL) when the disease comes back or becomes worse after treatment with prior medicines, one of which included bortezomib. MCL is cancer of type of white blood cell called lymphocytes that are in the lymph nodes.. are pregnant, plan to become pregnant, or become pregnant during treatment with lenalidomide capsules. See What is the most important information should know about lenalidomide capsules. are allergic to lenalidomide or any of the ingredients in lenalidomide capsules. See the end of this Medication Guide for complete list of ingredients in lenalidomide capsules.. have liver problems. have kidney problems or receive kidney dialysis treatment have thyroid problems. have had serious skin rash with thalidomide treatment. You should not take lenalidomide capsules.. are lactose intolerant. Lenalidomide capsules contain lactose. are breastfeeding. Do not breastfeed during treatment with lenalidomide capsules. It is not known if lenalidomide passes into your breast milk and can harm your baby. Take lenalidomide capsules exactly as prescribed and follow all the instructions of the Lenalidomide REMS program Swallow lenalidomide capsules whole with water time day. Do not open, break, or chew your capsules. Lenalidomide capsules may be taken with or without food. Take lenalidomide capsules at about the same time each day. Do not open or break lenalidomide capsules or handle them any more than needed. If powder from the lenalidomide capsule comes in contact with your skin, wash the skin right away with soap and water.If powder from the lenalidomide capsule comes in contact with the inside of your eyes, nose, or mouth, flush well with water. If powder from the lenalidomide capsule comes in contact with your skin, wash the skin right away with soap and water.. If powder from the lenalidomide capsule comes in contact with the inside of your eyes, nose, or mouth, flush well with water.. If you miss dose of lenalidomide capsules and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take doses at the same time.. If you take too much lenalidomide, call your healthcare provider right away.. See What is the most important information should know about lenalidomide capsules Females: Do not get pregnant and do not breastfeed while taking lenalidomide capsules. Males: Do not donate sperm. Do not share lenalidomide capsules with other people. It may cause birth defects and other serious problems.. Do not donate blood while you take lenalidomide capsules, during any breaks (interruptions) in your treatment, and for weeks after stopping lenalidomide capsules. If someone who is pregnant gets your donated blood, her baby may be exposed to lenalidomide and may be born with birth defects.. See What is the most important information should know about lenalidomide capsules Increased risk of death in people who have chronic lymphocytic leukemia (CLL). People with CLL who take lenalidomide capsules have an increased risk of death compared with people who take the medicine chlorambucil. Lenalidomide capsules may cause you to have serious heart problems that can lead to death, including atrial fibrillation, heart attack, or heart failure. You should not take lenalidomide capsules if you have CLL unless you are participating in controlled clinical trial. Risk of new cancers (malignancies). An increase in new (second) cancers has happened in patients who received lenalidomide capsules and melphalan, or blood stem cell transplant, including certain blood cancers, such as acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS) and certain other types of cancers of the skin and other organs. Talk with your healthcare provider about your risk of developing new cancers if you take lenalidomide capsules. Your healthcare provider will check you for new cancers during your treatment with lenalidomide capsules.. Severe liver problems, including liver failure and death. Your healthcare provider should do blood tests to check your liver function during your treatment with lenalidomide capsules. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:. yellowing of your skin or the white part of your eyes (jaundice). dark or brown (tea-colored) urine. pain on the upper right side of your stomach area (abdomen). bleeding or bruising more easily than normal. feeling very tired. Severe skin reactions and severe allergic reactions can happen with lenalidomide capsules and may cause death.. red, itchy, skin rash. peeling of your skin or blisters. severe itching. fever. swelling of your lips, mouth, tongue, or throat. trouble breathing or swallowing. raised red areas on your skin (hives). very fast heartbeat. you feel dizzy or faint. Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and sometimes death. Your healthcare provider may do blood tests to check you for TLS. Worsening of your tumor (tumor flare reaction). Tell your healthcare provider if you get any of these symptoms of tumor flare reaction while taking lenalidomide capsules: tender swollen lymph nodes, low grade fever, pain, or rash. Thyroid problems. Your healthcare provider may check your thyroid function before you start taking lenalidomide capsules and during treatment with lenalidomide capsules.. Risk of Early Death in MCL. In people who have Mantle Cell Lymphoma (MCL), there may be risk of dying sooner (early death) when taking lenalidomide capsules. Talk with your healthcare provider about any concerns and possible risk factors.. diarrhea. rash nausea. constipation. tiredness or weakness. fever. itching. swelling of your arms, hands, legs, feet and skin sleep problems (insomnia) headache. muscle cramps or spasms. shortness of breath. cough, sore throat, and other symptoms of cold. upper respiratory tract infection or bronchitis. inflammation of the stomach and intestine (stomach flu). nose bleed. shaking or trembling (tremor). joint aches. pain in your back or stomach-area (abdomen). Store lenalidomide capsules at room temperature between 68F to 77F (20C to 25C). Return any unused lenalidomide capsules to Teva or your healthcare provider.

SPL UNCLASSIFIED SECTION.

1.1 Multiple Myeloma. Lenalidomide capsules in combination with dexamethasone are indicated for the treatment of adult patients with multiple myeloma (MM).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2).. Lactation: Advise not to breastfeed (8.2).. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lenalidomide capsules during pregnancy as well as female partners of male patients who are exposed to lenalidomide capsules. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to lenalidomide capsules to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the Lenalidomide REMS program at 1-888-423-5436.Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies [see Data], lenalidomide can cause embryo-fetal harm when administered to pregnant female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4.1), and Use in Specific Populations (5.1)].Lenalidomide is thalidomide analogue. Thalidomide is human teratogen, inducing 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 [see Data]. 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 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 lenalidomide capsules to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the Lenalidomide REMS program at 1-888-423-5436.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.DataAnimal dataIn 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 pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed 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 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20% to 40% of the maternal Cmax. Following 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.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of lenalidomide in human milk, the effects of lenalidomide capsules on the breastfed child, or the effects of lenalidomide on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children from lenalidomide capsules, advise women not to breastfeed during treatment with lenalidomide capsules.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingLenalidomide capsules can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating lenalidomide capsules therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy weeks before therapy, while taking lenalidomide capsules, during dose interruptions and for at least weeks after completing therapy. Females of reproductive potential must have negative pregnancy tests before initiating lenalidomide capsules. The first test should be performed within 10 to 14 days, and the second test within 24 hours prior to prescribing lenalidomide capsules. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first weeks of use, then pregnancy testing should be repeated every weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every weeks. Pregnancy testing and counseling should be performed if patient misses her period or if there is any abnormality in her menstrual bleeding. Lenalidomide treatment must be discontinued during this evaluation. ContraceptionFemalesFemales of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use methods of reliable birth control simultaneously: one highly effective form of contraception tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partners vasectomy, and additional effective contraceptive method male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin weeks prior to initiating treatment with lenalidomide capsules, during therapy, during dose interruptions, and continuing for weeks following discontinuation of lenalidomide therapy. Reliable contraception is indicated even where there has been history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to qualified provider of contraceptive methods, if needed. Males Lenalidomide is present in the semen of males who take lenalidomide capsules. Therefore, males must always use latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to weeks after discontinuing lenalidomide capsules, even if they have undergone successful vasectomy. Male patients taking lenalidomide capsules must not donate sperm.. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.. 8.5 Geriatric Use. MM In Combination: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521/1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the adverse reaction categories (eg, all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was higher in older (> 75 years of age) than in younger (<= 75 years of age) subjects. Grade or adverse reactions in the General Disorders and Administration Site Conditions body system were consistently reported at higher frequency (with difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade or adverse reactions in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other body systems (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger subjects across all treatment arms Serious adverse reactions were generally reported at higher frequency in the older subjects than in the younger subjects across all treatment arms.MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received lenalidomide/dexamethasone, 46% were age 65 and over. In both studies, patients 65 years of age were more likely than patients <= 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide capsules. No differences in efficacy were observed between patients over 65 years of age and younger patients. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%). greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse reactions was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade and adverse reactions was also similar in these patient groups (79% vs. 78%, respectively). The frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.. 8.6 Renal Impairment. Adjust the starting dose of lenalidomide capsules based on the creatinine clearance value and for patients on dialysis [see Dosage and Administration (2.6)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with lenalidomide capsules (5.5). Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving lenalidomide capsules (5.6). Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and thalidomide analogue (5.7).Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop lenalidomide capsules and evaluate if hepatotoxicity is suspected (5.8). Severe Cutaneous Reactions: Discontinue lenalidomide for severe reactions (5.9). Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions (5.10). Tumor flare reaction: Serious tumor flare reactions have occurred during investigational use of lenalidomide capsules for chronic lymphocytic leukemia and lymphoma (5.11). Impaired Stem Cell mobilization: decrease in the number of CD34+ cells collected after treatment (> cycles) with lenalidomide has been reported. Consider early referral to transplant center (5.12). Early mortality in MCL: Higher rate of early deaths have occurred in patients with MCL (5.14). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue lenalidomide for angioedema and anaphylaxis (5.15).. Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with lenalidomide capsules (5.5). Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving lenalidomide capsules (5.6). Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and thalidomide analogue (5.7).. Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop lenalidomide capsules and evaluate if hepatotoxicity is suspected (5.8). Severe Cutaneous Reactions: Discontinue lenalidomide for severe reactions (5.9). Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions (5.10). Tumor flare reaction: Serious tumor flare reactions have occurred during investigational use of lenalidomide capsules for chronic lymphocytic leukemia and lymphoma (5.11). Impaired Stem Cell mobilization: decrease in the number of CD34+ cells collected after treatment (> cycles) with lenalidomide has been reported. Consider early referral to transplant center (5.12). Early mortality in MCL: Higher rate of early deaths have occurred in patients with MCL (5.14). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue lenalidomide for angioedema and anaphylaxis (5.15).. 5.1 Embryo-Fetal Toxicity. Lenalidomide is thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.Lenalidomide capsules are only available through the Lenalidomide REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least weeks before beginning lenalidomide capsules therapy, during therapy, during dose interruptions and for at least weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning weeks prior to initiating treatment with lenalidomide capsules, during therapy, during dose interruptions and continuing for weeks following discontinuation of lenalidomide therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10 to 14 days and the second test within 24 hours prior to prescribing lenalidomide therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every weeks in females with irregular menstrual cycles [see Use in Specific Populations (8.3)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to weeks after discontinuing lenalidomide capsules, even if they have undergone successful vasectomy. Male patients taking lenalidomide capsules must not donate sperm [see Use in Specific Populations (8.3)]. Blood Donation Patients must not donate blood during treatment with lenalidomide capsules and for weeks following discontinuation of the drug because the blood might be given to pregnant female patient whose fetus must not be exposed to lenalidomide.. 5.2 Lenalidomide REMS Program. Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], lenalidomide capsules are available only through restricted program under Risk Evaluation and Mitigation Strategy (REMS), the Lenalidomide REMS program. Required components of the Lenalidomide REMS program include the following: Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements. Patients must sign Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] and males must comply with contraception requirements [see Use in Specific Populations (8.3)]. Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive lenalidomide capsules and comply with REMS requirements. Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436.. Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements. Patients must sign Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] and males must comply with contraception requirements [see Use in Specific Populations (8.3)]. Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive lenalidomide capsules and comply with REMS requirements.. 5.3 Hematologic Toxicity. Lenalidomide capsules can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking lenalidomide capsules should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)].Monitor complete blood counts (CBC) in patients taking lenalidomide capsules in combination with dexamethasone for MM every days (weekly) for the first cycles, on Days and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)]. In trials for another indication, Grade or neutropenia was reported in up to 59% of lenalidomide capsules-treated patients and Grade or thrombocytopenia in up to 38% of lenalidomide capsules-treated patients.Monitor complete blood counts (CBC) in patients taking lenalidomide capsules for MDS weekly for the first weeks and at least monthly thereafter. Grade or hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade or neutropenia, the median time to onset was 42 days (range, 14 to 411 days), and the median time to documented recovery was 17 days (range, to 170 days). In the 54% of patients who developed Grade or thrombocytopenia, the median time to onset was 28 days (range, to 290 days), and the median time to documented recovery was 22 days (range, to 224 days) [see Boxed Warning and Dosage and Administration (2.2)]. Monitor complete blood counts (CBC) in patients taking lenalidomide capsules for MCL weekly for the first cycle (28 days), every weeks during cycles to 4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade or neutropenia was reported in 43% of the patients. Grade or thrombocytopenia was reported in 28% of the patients.. 5.4 Venous and Arterial Thromboembolism. Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with lenalidomide.A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with lenalidomide and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with lenalidomide capsules and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed MM who were treated with lenalidomide capsules and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patients underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on benefit-risk decision in patients receiving lenalidomide capsules [see Drug Interactions (7.2)].. 5.5 Increased Mortality in Patients with CLL. In prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent lenalidomide capsules therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the lenalidomide capsules treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 to 3.41], consistent with 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the lenalidomide capsules treatment arm. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials. 5.6 Second Primary Malignancies. In clinical trials in patients with MM receiving lenalidomide capsules, an increase of hematologic plus solid tumor second primary malignancies (SPM) notably AML and MDS have been observed. An increase in hematologic SPM including AML and MDS occurred in 5.3% of patients with NDMM receiving lenalidomide capsules in combination with oral melphalan compared with 1.3% of patients receiving melphalan without lenalidomide capsules. The frequency of AML and MDS cases in patients with NDMM treated with lenalidomide capsules in combination with dexamethasone without melphalan was 0.4%. In study for another indication, hematologic SPM occurred in 7.5% of patients compared to 3.3% in patients receiving placebo. The incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8% in patients receiving placebo with median follow-up of 91.5 months. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide capsules maintenance, compared to 2.6% in the placebo arm.In patients with relapsed or refractory MM treated with lenalidomide capsules/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving lenalidomide capsules/dexamethasone, compared to 0.6% in the dexamethasone alone arm.Patients who received lenalidomide-containing therapy until disease progression did not show higher incidence of invasive SPM than patients treated in the fixed duration lenalidomide-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of lenalidomide capsules and the risk of second primary malignancies when considering treatment with lenalidomide capsules.. 5.7 Increased Mortality in Patients with MM WhenPembrolizumab Is Added to Thalidomide Analogue and Dexamethasone. In two randomized clinical trials in patients with MM, the addition of pembrolizumab to thalidomide analogue plus dexamethasone, use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with PD-1 or PD-L1 blocking antibody in combination with thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.. 5.8 Hepatotoxicity. Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at lower dose may be considered.. 5.9 Severe Cutaneous Reactions. Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with prior history of Grade rash associated with thalidomide treatment should not receive lenalidomide capsules. Consider lenalidomide capsules interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue lenalidomide capsules for Grade rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5)]. 5.10 Tumor Lysis Syndrome. Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. Monitor patients at risk closely and take appropriate preventive approaches.. 5.11 Tumor Flare Reaction. Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade or in severity. All of the events occurred in Cycle and one patient developed TFR again in Cycle 11. Lenalidomide may be continued in patients with Grade and TFR without interruption or modification, at the physicians discretion. Patients with Grade and TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade or TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to <= Grade 1. Patients with Grade or TFR may be treated for management of symptoms per the guidance for treatment of Grade and TFR.. 5.12 Impaired Stem Cell Mobilization. decrease in the number of CD34+ cells collected after treatment (> cycles) with lenalidomide has been reported. In patients who are auto-HSCT candidates, referral to transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than cycles of lenalidomide-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with CXCR4 inhibitor may be considered.. 5.13 Thyroid Disorders. Both hypothyroidism and hyperthyroidism have been reported [see Adverse Reactions (6.2)]. Measure thyroid function before start of lenalidomide capsules treatment and during therapy.. 5.14 Early Mortality in Patients with MCL. In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the lenalidomide arm versus 7.1% in the control arm. On exploratory multivariate analysis, risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (>= 10 109/L).. 5.15 Hypersensitivity. Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide capsules have been reported. Permanently discontinue lenalidomide capsules for angioedema and anaphylaxis [see Dosage and Administration (2.2)].