Lenalidomide

1 INDICATIONS AND USAGE Lenalidomide capsules are a thalidomide analogue indicated for the treatment of adult patients with: • Multiple myeloma (MM), in combination with dexamethasone ( 1.1 ). • MM, as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT) ( 1.1 ). • Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities ( 1.2 ). • Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib ( 1.3 ). • Previously treated follicular lymphoma (FL), in combination with a rituximab product ( 1.4 ). • Previously treated marginal zone lymphoma (MZL), in combination with a rituximab product ( 1.5 ). 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 ). 1.1 Multiple Myeloma Lenalidomide capsules in combination with dexamethasone are indicated for the treatment of adult patients with multiple myeloma (MM). Lenalidomide capsules are indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). 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 a 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. 1.4 Follicular Lymphoma Lenalidomide capsules in combination with a rituximab product, are indicated for the treatment of adult patients with previously treated follicular lymphoma (FL). 1.5 Marginal Zone Lymphoma Lenalidomide capsules in combination with a rituximab product, are indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL). 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) ] .

2 DOSAGE AND ADMINISTRATION • MM combination therapy: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles ( 2.1 ). • MM maintenance therapy following auto-HSCT: 10 mg once daily continuously on Days 1-28 of repeated 28-day cycles ( 2.1 ). • MDS: 10 mg once daily ( Error! Hyperlink reference not valid. ). • MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles ( 2.3 ). • FL or MZL: 20 mg once daily orally on Days 1-21 of repeated 28-day cycles for up to 12 cycles ( 2.4 ). • Renal impairment: Adjust starting dose based on the creatinine clearance value ( 2.6 ). • For concomitant therapy doses, see Full Prescribing Information ( 2.1 , 2.4 , 14.1 , 14.4 ). 2.1 Recommended Dosage for Multiple Myeloma Lenalidomide Capsule Combination Therapy The recommended starting dose of lenalidomide capsules is 25 mg orally once daily on Days 1-21 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 4 cycles of a lenalidomide capsule-containing therapy [see Warnings and Precautions (5.12) ] . Dose Adjustments for Hematologic Toxicities During MM Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide capsules. Table 1: Dose Adjustments for Hematologic Toxicities for MM Platelet Counts Thrombocytopenia in MM When Platelets Recommended Course Days 1-21 of Repeated 28-day Cycle Fall below 30,000/mcL Interrupt lenalidomide capsule treatment, follow CBC weekly Return to at least 30,000/mcL Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily For each subsequent drop below 30,000/mcL Interrupt lenalidomide capsule treatment Return to at least 30,000/mcL Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily Absolute Neutrophil Counts (ANC) Neutropenia in MM When Neutrophils Recommended Course Days 1-21 of Repeated 28-day Cycle Fall below 1,000/mcL Interrupt lenalidomide capsule 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/mcL Interrupt lenalidomide capsule treatment Return to at least 1,000/mcL Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily Lenalidomide Capsule Maintenance Therapy Following Auto-HSCT Following auto-HSCT, initiate lenalidomide capsule maintenance therapy after adequate hematologic recovery (ANC at least 1,000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of lenalidomide capsules is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated. Dose Adjustments for Hematologic Toxicities During MM Treatment Dose modification guidelines, as summarized in Table 2 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide capsules. Table 2: Dose Adjustments for Hematologic Toxicities for MM Platelet Counts Thrombocytopenia in MM When Platelets Recommended Course Fall below 30,000/mcL Interrupt lenalidomide capsule treatment, follow CBC weekly Return to at least 30,000/mcL Resume lenalidomide capsules at next lower dose, continuously for Days 1-28 of repeated 28-day cycle If at the 5 mg daily dose, For a subsequent drop below 30,000/mcL Interrupt lenalidomide capsule treatment. Do not dose below 5 mg daily for Day 1 to 21 of 28-day cycle Return to at least 30,000/mcL Resume lenalidomide capsules at 5 mg daily for Days 1 to 21of 28-day cycle. Do not dose below 5 mg daily for Day 1 to 21 of 28-day cycle Absolute Neutrophil Counts (ANC) Neutropenia in MM When Neutrophils Recommended Course Fall below 500/mcL Interrupt lenalidomide capsule treatment, follow CBC weekly Return to at least 500/mcL Resume lenalidomide capsules at next lower dose, continuously for Days 1-28 of repeated 28-day cycle If at 5 mg daily dose, For a subsequent drop below 500/mcL Interrupt lenalidomide capsule treatment. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle Return to at least 500/mcL Resume lenalidomide capsules at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle 2.2 Recommended Dosage for Myelodysplastic Syndromes 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 Treatment Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows: Platelet Counts If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS: If baseline is at least 100,000/mcL When Platelets Recommended Course Fall below 50,000/mcL Interrupt lenalidomide capsule treatment Return to at least 50,000/mcL Resume lenalidomide capsules at 5 mg daily If baseline is below 100,000/mcL When Platelets Recommended Course Fall to 50% of the baseline value Interrupt lenalidomide capsule treatment If baseline is at least 60,000/mcL and returns to at least 50,000/mcL Resume lenalidomide capsules at 5 mg daily If baseline is below 60,000/mcL and returns to at least 30,000/mcL Resume lenalidomide capsules at 5 mg daily If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS: When Platelets Recommended Course Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions Interrupt lenalidomide capsule treatment Return to at least 30,000/mcL (without hemostatic failure) Resume lenalidomide capsules at 5 mg daily Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows: If thrombocytopenia develops during treatment at 5 mg daily in MDS: When Platelets Recommended Course Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions Interrupt lenalidomide capsule treatment Return to at least 30,000/mcL (without hemostatic failure) Resume lenalidomide capsules at 2.5 mg daily Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows: Absolute Neutrophil Counts (ANC) If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS: If baseline ANC is at least 1,000/mcL When Neutrophils Recommended Course Fall below 750/mcL Interrupt lenalidomide capsule treatment Return to at least 1,000/mcL Resume lenalidomide capsules at 5 mg daily If baseline ANC is below 1,000/mcL When Neutrophils Recommended Course Fall below 500/mcL Interrupt lenalidomide capsule treatment Return to at least 500/mcL Resume lenalidomide capsules at 5 mg daily If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS: When Neutrophils Recommended Course Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5°C) Interrupt lenalidomide capsule treatment Return to at least 500/mcL Resume lenalidomide capsules at 5 mg daily Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows: If neutropenia develops during treatment at 5 mg daily in MDS: When Neutrophils Recommended Course Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5°C) Interrupt lenalidomide capsule treatment Return to at least 500/mcL Resume 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 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to lenalidomide capsules. Platelet Counts Thrombocytopenia during treatment in MCL: When Platelets Recommended Course Fall below 50,000/mcL Interrupt lenalidomide capsule treatment and follow CBC weekly Return to at least 50,000/mcL Resume lenalidomide capsules at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil Counts (ANC) Neutropenia during treatment in MCL: When Neutrophils Recommended Course Fall below 1,000/mcL for at least 7 days OR Falls below 1,000/mcL with an associated temperature at least 38.5°C OR Falls below 500/mcL Interrupt lenalidomide capsule treatment and follow CBC weekly Return to at least 1,000/mcL Resume lenalidomide capsules at 5 mg less than the previous dose. Do not dose below 5 mg daily 2.4 Recommended Dosage for Follicular Lymphoma or Marginal Zone Lymphoma The recommended starting dose of lenalidomide capsules is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab product. Refer to Section 14.4 for specific rituximab dosing from the AUGMENT trial. For dose adjustments due to toxicity with rituximab, refer to the product prescribing information. Dose Adjustments for Hematologic Toxicities During FL or MZL Treatment Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide capsules. Platelet Counts Thrombocytopenia during treatment in FL or MZL: When Platelets Recommended Course Fall below 50,000/mcL Interrupt lenalidomide capsule treatment and follow CBC weekly. Return to at least 50,000/mcL If patient starting dose was 20 mg daily, resume lenalidomide capsules at 5 mg less than the previous dose. Do not dose below 5 mg daily. If patient starting dose was 10 mg daily, resume at 5 mg less than previous dose. Do not dose below 2.5 mg daily. Absolute Neutrophil Counts (ANC) Neutropenia during treatment in FL or MZL: When Neutrophils Recommended Course Fall below 1,000/mcL for at least 7 days OR Falls below 1,000/mcL with an associated temperature at least 38.5°C OR Falls below 500/mcL Interrupt lenalidomide capsule treatment and follow CBC weekly. Return to at least 1,000/mcL If patient starting dose was 20 mg daily, resume lenalidomide capsules at 5 mg less than the previous dose. Do not dose below 5 mg daily. If patient starting dose was 10 mg daily, resume at 5 mg less than previous dose. Do not dose below 2.5 mg daily. 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions For non-hematologic Grade 3/4 toxicities judged to be related to lenalidomide capsules, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to Grade 2 or below. Permanently discontinue lenalidomide capsules for angioedema, anaphylaxis, Grade 4 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 Renal Impairment 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 Impairment Renal Function (Cockcroft-Gault) Dose in Lenalidomide Capsule Combination Therapy for MM and MCL Dose in Lenalidomide Capsule Combination Therapy for FL and MZL Dose in Lenalidomide Capsule Maintenance Therapy Following Auto-HSCT for MM and for MDS CLcr 30 to 60 mL/min 10 mg once daily 10 mg once daily 5 mg once daily CLcr below 30 mL/min (not requiring dialysis) 15 mg every other day 5 mg once daily 2.5 mg once daily CLcr below 30 mL/min (requiring dialysis) 5 mg once daily. On dialysis days, administer the dose following dialysis. 5 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 Capsule Combination Therapy for MM For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. Lenalidomide Capsule Maintenance Therapy Following Auto-HSCT for MM and for MCL and MDS Base subsequent lenalidomide capsule dose increase or decrease on individual patient treatment tolerance [see Dosage and Administration (2.1 , Error! Hyperlink reference not valid. , 2.3) ] . Lenalidomide Capsule Combination Therapy for FL or for MZL For patients with CLcr of 30 to 60 mL/min, after 2 cycles, the lenalidomide capsule dose may be increased to 15 mg orally if the patient has tolerated therapy. 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.

4 CONTRAINDICATIONS • 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 a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning ] . If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus [see Warnings and Precautions (5.1 , 5.2) , Use in Special Populations (8.1 , 8.3) ] . 4.2 Severe Hypersensitivity Reactions 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) ] .

Not available.

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 a 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-Hodgkin’s Lymphoma (NHL: MCL, FL or MZL): Most common adverse reactions (≥ 15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed MM – Lenalidomide Capsule Combination Therapy Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide capsules with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N = 532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N = 540] or who received melphalan, prednisone and thalidomide (Arm MPT; N = 541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of lenalidomide capsules were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide capsules was 7 weeks. The most common adverse reactions leading to dose reduction of lenalidomide capsules in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide capsules was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide capsules were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥ 5% and Grade 3/4 Adverse Reactions in ≥ 1% of Patients with MM in the Rd Continuous or Rd18 Arms Adverse reactions included in combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. All Adverse Reactions All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. Grade 3/4 Adverse Reactions All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. Body System Adverse Reaction 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 - 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). 173 (33) 177 (33) 154 (28) 39 (7) 46 (9) 31 (6) Asthenia 150 (28) 123 (23) 124 (23) 41 (8) 33 (6) 32 (6) Pyrexia Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. 114 (21) 102 (19) 76 (14) 13 (2) 7 (1) 7 (1) Non-cardiac chest pain Footnote “b” not applicable. 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 109 (20) 78 (14) 60 (11) 7 (1) 9 (2) < 1% Dyspepsia 57 (11) 28 (5) 36 (7) < 1% < 1% 0 (0) Musculoskeletal and connective tissue disorders Back pain 170 (32) 145 (27) 116 (21) 37 (7) 34 (6) 28 (5) Muscle spasms 109 (20) 102 (19) 61 (11) < 1% < 1% < 1% Arthralgia 101 (19) 71 (13) 66 (12) 9 (2) 8 (1) 8 (1) Bone pain 87 (16) 77 (14) 62 (11) 16 (3) 15 (3) 14 (3) Pain in extremity 79 (15) 66 (12) 61 (11) 8 (2) 8 (1) 7 (1) Musculoskeletal pain 67 (13) 59 (11) 36 (7) < 1% < 1% < 1% Musculoskeletal chest pain 60 (11) 51 (9) 39 (7) 6 (1) < 1% < 1% Muscular weakness 43 (8) 35 (6) 29 (5) < 1% 8 (1) < 1% Neck pain 40 (8) 19 (4) 10 (2) < 1% < 1% < 1% Infections and infestations Bronchitis 90 (17) 59 (11) 43 (8) 9 (2) 6 (1) < 1% Nasopharyngitis 80 (15) 54 (10) 33 (6) 0 (0) 0 (0) 0 (0) Urinary tract infection 76 (14) 63 (12) 41 (8) 8 (2) 8 (1) < 1% Upper respiratory tract infection 69 (13) 53 (10) 31 (6) < 1% 8 (1) < 1% Pneumonia - adverse reactions in which at least one resulted in a fatal outcome. 93 (17) 87 (16) 56 (10) 60 (11) 57 (11) 41 (8) Respiratory tract infection 35 (7) 25 (5) 21 (4) 7 (1) < 1% < 1% Influenza 33 (6) 23 (4) 15 (3) < 1% < 1% 0 (0) Gastroenteritis 32 (6) 17 (3) 13 (2) 0 (0) < 1% < 1% Lower respiratory tract infection 29 (5) 14 (3) 16 (3) 10 (2) < 1% < 1% Rhinitis 29 (5) 24 (4) 14 (3) 0 (0) 0 (0) 0 (0) Cellulitis < 5% < 5% < 5% 8 (2) < 1% < 1% Sepsis 33 (6) 26 (5) 18 (3) 26 (5) 20 (4) 13 (2) Nervous system disorders Headache 75 (14) 52 (10) 56 (10) < 1% < 1% < 1% Dysgeusia 39 (7) 45 (8) 22 (4) < 1% 0 (0) < 1% Blood and lymphatic system disorders 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. Anemia 233 (44) 193 (36) 229 (42) 97 (18) 85 (16) 102 (19) Neutropenia 186 (35) 178 (33) 328 (61) 148 (28) 143 (26) 243 (45) Thrombocytopenia 104 (20) 100 (19) 135 (25) 44 (8) 43 (8) 60 (11) Febrile neutropenia 7 (1) 17 (3) 15 (3) 6 (1) 16 (3) 14 (3) Pancytopenia < 1% 6 (1) 7 (1) < 1% < 1% < 1% Respiratory, thoracic and mediastinal disorders Cough 121 (23) 94 (17) 68 (13) < 1% < 1% < 1% Dyspnea Footnote “a” not applicable. 117 (22) 89 (16) 113 (21) 30 (6) 22 (4) 18 (3) Epistaxis 32 (6) 31 (6) 17 (3) < 1% < 1% 0 (0) Oropharyngeal pain 30 (6) 22 (4) 14 (3) 0 (0) 0 (0) 0 (0) Dyspnea exertional 27 (5) 29 (5) < 5% 6 (1) < 1% 0 (0) Metabolism and nutrition disorders Decreased appetite 123 (23) 115 (21) 72 (13) 14 (3) 7 (1) < 1% Hypokalemia 91 (17) 62 (11) 38 (7) 35 (7) 20 (4) 11 (2) Hyperglycemia 62 (12) 52 (10) 19 (4) 28 (5) 23 (4) 9 (2) Hypocalcemia 57 (11) 56 (10) 31 (6) 23 (4) 19 (4) 8 (1) Dehydration 25 (5) 29 (5) 17 (3) 8 (2) 13 (2) 9 (2) Gout < 5% < 5% < 5% 8 (2) 0 (0) 0 (0) Diabetes mellitus < 5% < 5% < 5% 8 (2) < 1% < 1% Hypophosphatemia < 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 thrombosis 55 (10) 39 (7) 22 (4) 30 (6) 20 (4) 15 (3) Hypotension 51 (10) 35 (6) 36 (7) 11 (2) 8 (1) 6 (1) Injury, Poisoning, and Procedural Complications Fall 43 (8) 25 (5) 25 (5) < 1% 6 (1) 6 (1) Contusion 33 (6) 24 (4) 15 (3) < 1% < 1% 0 (0) Eye disorders Cataract 73 (14) 31 (6) < 1% 31 (6) 14 (3) < 1% Cataract subcapsular < 5% < 5% < 5% 7 (1) 0 (0) 0 (0) Investigations Weight decreased 72 (14) 78 (14) 48 (9) 11 (2) < 1% < 1% Cardiac disorders Atrial fibrillation 37 (7) 25 (5) 25 (5) 13 (2) 9 (2) 6 (1) Myocardial infarction (including acute) < 5% < 5% < 5% 10 (2) < 1% < 1% Renal and Urinary disorders Renal failure (including acute) 49 (9) 54 (10) 37 (7) 28 (5) 33 (6) 29 (5) Neoplasms benign, malignant and unspecified (including cysts and polyps) Squamous cell carcinoma < 5% < 5% < 5% 8 (2) < 1% 0 (0) Basal cell carcinoma < 5% < 5% < 5% < 1% < 1% 0 (0) Newly Diagnosed MM – Lenalidomide Capsule Maintenance Therapy Following Auto-HSCT Data were evaluated from 1018 patients in two randomized trials who received at least one dose of lenalidomide capsules 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for lenalidomide capsule treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 lenalidomide capsules arm were still on treatment and none of the patients in the Maintenance Study 2 lenalidomide capsules arm were still on treatment at the same cut-off date. The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan/auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the lenalidomide capsules arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the lenalidomide capsules arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the lenalidomide capsules arm. For lenalidomide capsules, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of lenalidomide capsules were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of lenalidomide capsules were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2. The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment. Table 5 summarizes the adverse reactions reported for the lenalidomide capsules and placebo maintenance treatment arms. Table 5: All Adverse Reactions in ≥ 5% and Grade 3/4 Adverse Reactions in ≥ 1% of Patients with MM in the Lenalidomide Capsules vs Placebo Arms Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): Pneumonias: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis Body System Adverse Reaction Maintenance Study 1 Maintenance Study 2 All Adverse Reactions All treatment-emergent AEs in at least 5% of patients in the Lenalidomide Capsule Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. Grade 3/4 Adverse Reactions All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the Lenalidomide Capsule Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. All Adverse Reactions Grade 3/4 Adverse Reactions Lenalidomide Capsules (N = 224) n (%) Placebo (N = 221) n (%) Lenalidomide Capsules (N = 224) n (%) Placebo (N = 221) n (%) Lenalidomide Capsules (N = 293) n (%) Placebo (N = 280) n (%) Lenalidomide Capsules (N = 293) n (%) Placebo (N = 280) n (%) Blood and lymphatic system disorders Neutropenia All serious treatment-emergent AEs in at least 1% of patients in the Lenalidomide Capsule Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. - ADRs where at least one was considered to be life-threatening (if the outcome of the event was death, it is included with death cases) 177 (79) 94 (43) 133 (59) 73 (33) 178 (61) 33 (12) 158 (54) 21 (8) Thrombocytopenia 162 (72) 101 (46) 84 (38) 67 (30) 69 (24) 29 (10) 38 (13) 8 (3) Leukopenia 51 (23) 25 (11) 45 (20) 22 (10) 93 (32) 21 (8) 71 (24) 5 (2) Anemia 47 (21) 27 (12) 23 (10) 18 (8) 26 (9) 15 (5) 11 (4) 3 (1) Lymphopenia 40 (18) 29 (13) 37 (17) 26 (12) 13 (4) 3 (1) 11 (4) < 1% Pancytopenia Footnote “a” not applicable for either study < 1% 0 (0) 0 (0) 0 (0) 12 (4) < 1% 7 (2) < 1% Febrile neutropenia 39 (17) 34 (15) 39 (17) 34 (15) 7 (2) < 1% 5 (2) < 1% Infections and infestations - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed Upper respiratory tract infection Footnote “b” not applicable for either study 60 (27) 35 (16) 7 (3) 9 (4) 32 (11) 18 (6) < 1% 0 (0) Neutropenic infection 40 (18) 19 (9) 27 (12) 14 (6) 0 (0) 0 (0) 0 (0) 0 (0) Pneumonias 31 (14) 15 (7) 23 (10) 7 (3) 50 (17) 13 (5) 27 (9) 5 (2) Bronchitis 10 (4) 9 (4) < 1% 5 (2) 139 (47) 104 (37) 4 (1) < 1% Nasopharyngitis 5 (2) < 1% 0 (0) 0 (0) 102 (35) 84 (30) < 1% 0 (0) Gastroenteritis 0 (0) 0 (0) 0 (0) 0 (0) 66 (23) 55 (20) 6 (2) 0 (0) Rhinitis < 1% 0 (0) 0 (0) 0 (0) 44 (15) 19 (7) 0 (0) 0 (0) Sinusitis 8 (4) 3 (1) 0 (0) 0 (0) 41 (14) 26 (9) 0 (0) < 1% Influenza 8 (4) 5 (2) < 1% < 1% 39 (13) 19 (7) 3 (1) 0 (0) Lung infection 21 (9) < 1% 19 (8) < 1% 9 (3) 4 (1) < 1% 0 (0) Lower respiratory tract infection 13 (6) 5 (2) 6 (3) 4 (2) 4 (1) 4 (1) 0 (0) < 1% Infection 12 (5) 6 (3) 9 (4) 5 (2) 17 (6) 5 (2) 0 (0) 0 (0) Urinary tract infection 9 (4) 5 (2) 4 (2) 4 (2) 22 (8) 17 (6) < 1% 0 (0) Lower respiratory tract infection bacterial 6 (3) < 1% 4 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Bacteremia 5 (2) 0 (0) 4 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Herpes zoster 11 (5) 10 (5) 3 (1) < 1% 29 (10) 25 (9) 6 (2) < 1% Sepsis - ADRs where at least one resulted in a fatal outcome < 1% < 1% 0 (0) 0 (0) 6 (2) < 1% 4 (1) < 1% Gastrointestinal disorders Diarrhea 122 (54) 83 (38) 22 (10) 17 (8) 114 (39) 34 (12) 7 (2) 0 (0) Nausea 33 (15) 22 (10) 16 (7) 10 (5) 31 (11) 28 (10) 0 (0) 0 (0) Vomiting 17 (8) 12 (5) 8 (4) 5 (2) 16 (5) 15 (5) < 1% 0 (0) Constipation 12 (5) 8 (4) 0 (0) 0 (0) 37 (13) 25 (9) < 1% 0 (0) Abdominal pain 8 (4) 7 (3) < 1% 4 (2) 31 (11) 15 (5) < 1% < 1% Abdominal pain upper 0 (0) 0 (0) 0 (0) 0 (0) 20 (7) 12 (4) < 1% 0 (0) General disorders and administration site conditions Asthenia 0 (0) < 1% 0 (0) 0 (0) 87 (30) 53 (19) 10 (3) < 1% Fatigue 51 (23) 30 (14) 21 (9) 9 (4) 31 (11) 15 (5) 3 (1) 0 (0) Pyrexia 17 (8) 10 (5) < 1% < 1% 60 (20) 26 (9) < 1% 0 (0) Skin and subcutaneous tissue disorders Dry skin 9 (4) 4 (2) 0 (0) 0 (0) 31 (11) 21 (8) 0 (0) 0 (0) Rash 71 (32) 48 (22) 11 (5) 5 (2) 22 (8) 17 (6) 3 (1) 0 (0) Pruritus 9 (4) 4 (2) 3 (1) 0 (0) 21 (7) 25 (9) < 1% 0 (0) Nervous system disorders Paresthesia < 1% 0 (0) 0 (0) 0 (0) 39 (13) 30 (11) < 1% 0 (0) Peripheral neuropathy 34 (15) 30 (14) 8 (4) 8 (4) 29 (10) 15 (5) 4 (1) < 1% Headache 11 (5) 8 (4) 5 (2) < 1% 25 (9) 21 (8) 0 (0) 0 (0) Investigations Alanine aminotransferase increased 16 (7) 3 (1) 8 (4) 0 (0) 5 (2) 5 (2) 0 (0) < 1% Aspartate aminotransferase increased 13 (6) 5 (2) 6 (3) 0 (0) < 1% 5 (2) 0 (0) 0 (0) Metabolism and nutrition disorders Hypokalemia 24 (11) 13 (6) 16 (7) 12 (5) 12 (4) < 1% < 1% 0 (0) Dehydration 9 (4) 5 (2) 7 (3) 3 (1) 0 (0) 0 (0) 0 (0) 0 (0) Hypophosphatemia 16 (7) 15 (7) 13 (6) 14 (6) 0 (0) < 1% 0 (0) 0 (0) Musculoskeletal and connective tissue disorders Muscle spasms 0 (0) < 1% 0 (0) 0 (0) 98 (33) 43 (15) < 1% 0 (0) Myalgia 7 (3) 8 (4) 3 (1) 5 (2) 19 (6) 12 (4) < 1% < 1% Musculoskeletal pain < 1% < 1% 0 (0) 0 (0) 19 (6) 11 (44) 0 (0) 0 (0) Hepatobiliary disorders Hyperbilirubinemia 34 (15) 19 (9) 4 (2) < 1% 4 (1) < 1% < 1% 0 (0) Respiratory, thoracic and mediastinal disorders Cough 23 (10) 12 (5) 3 (1) < 1% 80 (27) 56 (20) 0 (0) 0 (0) Dyspnea 15 (7) 9 (4) 8 (4) 4 (2) 17 (6) 9 (3) < 1% 0 (0) Rhinorrhea 0 (0) 3 (1) 0 (0) 0 (0) 15 (5) 6 (2) 0 (0) 0 (0) Pulmonary embolism 0 (0) 0 (0) 0 (0) 0 (0) 3 (1) 0 (0) < 1% 0 (0) Vascular disorders Deep vein thrombosis 8 (4) < 1% 5 (2) < 1% 7 (2) < 1% 4 (1) < 1% Neoplasms benign, malignant and unspecified (including cysts and polyps) Myelodysplastic syndrome 5 (2) 0 (0) < 1% 0 (0) 3 (1) 0 (0) < 1% 0 (0) After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of lenalidomide capsules/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the lenalidomide capsules/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of lenalidomide capsules compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the lenalidomide capsules/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of lenalidomide capsules/dexamethasone compared to placebo/dexamethasone. Tables 6, 7, and 8 summarize the adverse reactions reported for lenalidomide capsules/dexamethasone and placebo/dexamethasone groups. Table 6: Adverse Reactions Reported in ≥ 5% of Patients and with a ≥ 2% Difference in Proportion of Patients with MM Between the Lenalidomide Capsules/Dexamethasone and Placebo/Dexamethasone Groups Body System Adverse Reaction Lenalidomide Capsules/Dex (N = 353) n (%) Placebo/Dex (N = 350) n (%) Blood and lymphatic system disorders Neutropenia - 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). 149 (42) 22 (6) Anemia - adverse reactions in which at least one resulted in a fatal outcome. 111 (31) 83 (24) Thrombocytopenia 76 (22) 37 (11) Leukopenia 28 (8) 4 (1) Lymphopenia 19 (5) 5 (1) General disorders and administration site conditions Fatigue 155 (44) 146 (42) Pyrexia 97 (27) 82 (23) Peripheral edema 93 (26) 74 (21) Chest pain 29 (8) 20 (6) Lethargy 24 (7) 8 (2) Gastrointestinal disorders Constipation 143 (41) 74 (21) Diarrhea 136 (39) 96 (27) Nausea 92 (26) 75 (21) Vomiting 43 (12) 33 (9) Abdominal pain 35 (10) 22 (6) Dry mouth 25 (7) 13 (4) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33) 74 (21) Back pain 91 (26) 65 (19) Bone pain 48 (14) 39 (11) Pain in limb 42 (12) 32 (9) Nervous system disorders Dizziness 82 (23) 59 (17) Tremor 75 (21) 26 (7) Dysgeusia 54 (15) 34 (10) Hypoesthesia 36 (10) 25 (7) Neuropathy 23 (7) 13 (4) Respiratory, thoracic and mediastinal disorders Dyspnea 83 (24) 60 (17) Nasopharyngitis 62 (18) 31 (9) Pharyngitis 48 (14) 33 (9) Bronchitis 40 (11) 30 (9) Infections and infestations Upper respiratory tract infection 87 (25) 55 (16) Pneumonia 48 (14) 29 (8) Urinary tract infection 30 (8) 19 (5) Sinusitis 26 (7) 16 (5) Skin and subcutaneous system disorders Rash 75 (21) 33 (9) Sweating increased 35 (10) 25 (7) Dry skin 33 (9) 14 (4) Pruritus 27 (8) 18 (5) Metabolism and nutrition disorders Anorexia 55 (16) 34 (10) Hypokalemia 48 (14) 21 (6) Hypocalcemia 31 (9) 10 (3) Appetite decreased 24 (7) 14 (4) Dehydration 23 (7) 15 (4) Hypomagnesemia 24 (7) 10 (3) Investigations Weight decreased 69 (20) 52 (15) Eye disorders Blurred vision 61 (17) 40 (11) Vascular disorders Deep vein thrombosis 33 (9) 15 (4) Hypertension 28 (8) 20 (6) Hypotension 25 (7) 15 (4) Table 7: Grade 3/4 Adverse Reactions Reported in ≥ 2% Patients and with a ≥ 1% Difference in Proportion of Patients with MM Between the Lenalidomide Capsules/Dexamethasone and Placebo/Dexamethasone Groups Body System Adverse Reaction Lenalidomide Capsules/Dex (N = 353) n (%) Placebo/Dex (N = 350) n (%) Blood and lymphatic system disorders Neutropenia - 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). 118 (33) 12 (3) Thrombocytopenia - adverse reactions in which at least one resulted in a fatal outcome. 43 (12) 22 (6) Anemia 35 (10) 20 (6) Leukopenia 14 (4) < 1% Lymphopenia 10 (3) 4 (1) Febrile neutropenia 8 (2) 0 (0) General disorders and administration site conditions Fatigue 23 (7) 17 (5) Vascular disorders Deep vein thrombosis 29 (8) 12 (3) Infections and infestations Pneumonia 30 (8) 19 (5) Urinary tract infection 5 (1) < 1% Metabolism and nutrition disorders Hypokalemia 17 (5) 5 (1) Hypocalcemia 13 (4) 6 (2) Hypophosphatemia 9 (3) 0 (0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism 14 (4) < 1% Respiratory distress 4 (1) 0 (0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (6) 10 (3) Gastrointestinal disorders Diarrhea 11 (3) 4 (1) Constipation 7 (2) < 1% Nausea 6 (2) < 1% Cardiac disorders Atrial fibrillation 13 (4) 4 (1) Tachycardia 6 (2) < 1% Cardiac failure congestive 5 (1) < 1% Nervous system disorders Syncope 10 (3) < 1% Dizziness 7 (2) < 1% Eye disorders Cataract 6 (2) < 1% Cataract unilateral 5 (1) 0 (0) Psychiatric disorder Depression 10 (3) 6 (2) Table 8: Serious Adverse Reactions Reported in ≥ 1% Patients and with a ≥ 1% Difference in Proportion of Patients with MM Between the Lenalidomide Capsules/Dexamethasone and Placebo/Dexamethasone Groups Body System Adverse Reaction Lenalidomide Capsules/Dex (N = 353) n (%) Placebo/Dex (N = 350) n (%) Blood and lymphatic system disorders Febrile neutropenia - 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). 6 (2) 0 (0) Vascular disorders Deep vein thrombosis 26 (7) 11 (3) Infections and infestations Pneumonia - adverse reactions in which at least one resulted in a fatal outcome. 33 (9) 21 (6) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism 13 (4) < 1% Cardiac disorders Atrial fibrillation 11 (3) < 1% Cardiac failure congestive 5 (1) 0 (0) Nervous system disorders Cerebrovascular accident 7 (2) < 1% Gastrointestinal disorders Diarrhea 6 (2) < 1% Musculoskeletal and connective tissue disorders Bone pain 4 (1) 0 (0) Median duration of exposure among patients treated with lenalidomide capsules/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 capsules/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 a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the lenalidomide capsules/dexamethasone group compared to 3.1% and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both < 1%). Interruption of lenalidomide capsule treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the lenalidomide capsules/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively). Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the lenalidomide capsules/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 capsules/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the lenalidomide capsules/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 capsules/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6%, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions After At Least One Prior Therapy for MM: In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥ 1% rate and of at least twice of the placebo percentage rate were reported: Blood and Lymphatic System Disorders: pancytopenia, autoimmune hemolytic anemia Cardiac Disorders: bradycardia, myocardial infarction, angina pectoris Endocrine Disorders: hirsutism Eye Disorders: blindness, ocular hypertension Gastrointestinal Disorders: gastrointestinal hemorrhage, glossodynia General Disorders and Administration Site Conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous System Disorders: cerebral ischemia Psychiatric Disorders: mood swings, hallucination, loss of libido Reproductive System and Breast Disorders: erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: cough, hoarseness Skin and Subcutaneous Tissue Disorders: exanthem, skin hyperpigmentation Myelodysplastic Syndromes A total of 148 patients received at least 1 dose of 10 mg lenalidomide capsules 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 9 summarizes the adverse reactions that were reported in ≥ 5% of the lenalidomide capsule-treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with lenalidomide capsules. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient’s underlying disease. Table 9: Summary of Adverse Reactions Reported in ≥ 5% of the Lenalidomide Capsule-Treated Patients in del 5q MDS Clinical Study Body System Adverse Reaction Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. 10 mg Overall (N = 148) Patients with at least one adverse reaction 148 (100) Blood and Lymphatic System Disorders Thrombocytopenia 91 (61) Neutropenia 87 (59) Anemia 17 (11) Leukopenia 12 (8) Febrile Neutropenia 8 (5) Skin and Subcutaneous Tissue Disorders Pruritus 62 (42) Rash 53 (36) Dry Skin 21 (14) Contusion 12 (8) Night Sweats 12 (8) Sweating Increased 10 (7) Ecchymosis 8 (5) Erythema 8 (5) Gastrointestinal Disorders Diarrhea 72 (49) Constipation 35 (24) Nausea 35 (24) Abdominal Pain 18 (12) Vomiting 15 (10) Abdominal Pain Upper 12 (8) Dry Mouth 10 (7) Loose Stools 9 (6) Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis 34 (23) Cough 29 (20) Dyspnea 25 (17) Pharyngitis 23 (16) Epistaxis 22 (15) Dyspnea Exertional 10 (7) Rhinitis 10 (7) Bronchitis 9 (6) General Disorders and Administration Site Conditions Fatigue 46 (31) Pyrexia 31 (21) Edema Peripheral 30 (20) Asthenia 22 (15) Edema 15 (10) Pain 10 (7) Rigors 9 (6) Chest Pain 8 (5) Musculoskeletal and Connective Tissue Disorders Arthralgia 32 (22) Back Pain 31 (21) Muscle Cramp 27 (18) Pain in Limb 16 (11) Myalgia 13 (9) Peripheral Swelling 12 (8) Nervous System Disorders Dizziness 29 (20) Headache 29 (20) Hypoesthesia 10 (7) Dysgeusia 9 (6) Peripheral Neuropathy 8 (5) Infections and Infestations Upper Respiratory Tract Infection 22 (15) Pneumonia 17 (11) Urinary Tract Infection 16 (11) Sinusitis 12 (8) Cellulitis 8 (5) Metabolism and Nutrition Disorders Hypokalemia 16 (11) Anorexia 15 (10) Hypomagnesemia 9 (6) Investigations Alanine Aminotransferase Increased 12 (8) Psychiatric Disorders Insomnia 15 (10) Depression 8 (5) Renal and Urinary Disorders Dysuria 10 (7) Vascular Disorders Hypertension 9 (6) Endocrine Disorders Acquired Hypothyroidism 10 (7) Cardiac Disorders Palpitations 8 (5) Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions Adverse reactions with frequency ≥ 1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study Adverse Reactions Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. 10 mg (N = 148) Patients with at least one Grade 3/4 AE 131 (89) Neutropenia 79 (53) Thrombocytopenia 74 (50) Pneumonia 11 (7) Rash 10 (7) Anemia 9 (6) Leukopenia 8 (5) Fatigue 7 (5) Dyspnea 7 (5) Back Pain 7 (5) Febrile Neutropenia 6 (4) Nausea 6 (4) Diarrhea 5 (3) Pyrexia 5 (3) Sepsis 4 (3) Dizziness 4 (3) Granulocytopenia 3 (2) Chest Pain 3 (2) Pulmonary Embolism 3 (2) Respiratory Distress 3 (2) Pruritus 3 (2) Pancytopenia 3 (2) Muscle Cramp 3 (2) Respiratory Tract Infection 2 (1) Upper Respiratory Tract Infection 2 (1) Asthenia 2 (1) Multi-organ Failure 2 (1) Epistaxis 2 (1) Hypoxia 2 (1) Pleural Effusion 2 (1) Pneumonitis 2 (1) Pulmonary Hypertension 2 (1) Vomiting 2 (1) Sweating Increased 2 (1) Arthralgia 2 (1) Pain in Limb 2 (1) Headache 2 (1) Syncope 2 (1) In other clinical studies of lenalidomide capsules in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported: Blood and Lymphatic System Disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia Cardiac Disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction Ear and Labyrinth Disorders: vertigo Endocrine Disorders: Basedow’s disease Gastrointestinal Disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage General Disorders and Administration Site Conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death Hepatobiliary Disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure Immune System Disorders: hypersensitivity Infections and Infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis Injury, Poisoning and Procedural Complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased Metabolism and Nutrition Disorders: dehydration, gout, hypernatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate Neoplasms Benign, Malignant and Unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic Nervous System Disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack Psychiatric Disorders: confusional state Renal and Urinary Disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass Reproductive System and Breast Disorders: pelvic pain Respiratory, Thoracic and Mediastinal Disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing Skin and Subcutaneous Tissue Disorders: acute febrile neutrophilic dermatosis Vascular System Disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of lenalidomide capsules. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with lenalidomide capsules. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions. Table 11: Incidence of Adverse Reactions (≥ 10%) or Grade 3/4 AE (in at Least 2 Patients) in Mantle Cell Lymphoma # - All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed. Body System Adverse Reaction All Adverse Reactions - MCL trial AEs – All treatment emergent AEs with ≥ 10% of subjects. (N = 134) n (%) Grade 3/4 Adverse Reactions - MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects. (N = 134) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia - MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects. 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea 42 (31) 8 (6) Nausea 40 (30) 1 (< 1) Constipation 21 (16) 1 (< 1) Vomiting 16 (12) 1 (< 1) Abdominal pain 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (< 1) Arthralgia 11 (8) 2 (1) Muscular weakness 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (< 1) Dyspnea 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia - Adverse reactions where at least one resulted in a fatal outcome. , 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis 3 (2) 2 (1) Bacteremia 2 (1) 2 (1) Staphylococcal sepsis 2 (1) 2 (1) Urinary tract infection 5 (4) 2 (1) Skin and subcutaneous tissue disorders Rash - All adverse reactions under HLT of Rash will be considered listed. 30 (22) 2 (1) Pruritus 23 (17) 1 (< 1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia - 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). , 48 (36) 37 (28) Anemia 41 (31) 15 (11) Leukopenia 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (< 1) Hypokalemia 17 (13) 3 (2) Dehydration 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure 5 (4) 2 (1) Vascular disorders Hypotension , 9 (7) 4 (3) Deep vein thrombosis 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in patients treated with lenalidomide capsule monotherapy for mantle cell lymphoma. Cardiac Disorders: Cardiac failure Ear and Labyrinth Disorders: Vertigo General Disorders and Administration Site Conditions: Chills Infections and Infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes Musculoskeletal and Connective Tissue Disorders: Pain in extremity Nervous System Disorders: Dysgeusia, headache, neuropathy peripheral, lethargy Psychiatric Disorders: Insomnia Skin and Subcutaneous Tissue Disorders: Dry skin, night sweats The following serious adverse reactions not described above and reported in 2 or more patients treated with lenalidomide capsule monotherapy for mantle cell lymphoma. Blood and Lymphatic System Disorders: Neutropenia Cardiac Disorders: Myocardial infarction (including acute MI), supraventricular tachycardia Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): Basal cell carcinoma Respiratory, Thoracic, and Mediastinal Disorders: Chronic obstructive pulmonary disease, pulmonary embolism Follicular Lymphoma or Marginal Zone Lymphoma The safety of lenalidomide capsules/rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N = 176) and MAGNIFY (N = 222) [see Clinical Studies (14.4) ] . Subjects were 18 years or older in age, had an ECOG PS ≤ 2, ANC ≥ 1,000 cells/mm 3 and platelets ≥ 75,000/mm 3 (unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥ 8 g/dL, AST and ALT ≤ 3x ULN (unless documented liver involvement with lymphoma, and creatinine clearance of ≥ 30 mL/min. Subjects with active HIV, hepatitis B or C were not eligible. In the AUGMENT trial, patients received lenalidomide capsules 20 mg daily by mouth on days 1-21 of each 28-day cycle with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n = 176) or placebo with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n = 180) for up to 12 cycles. In the MAGNIFY trial, patients received lenalidomide capsules 20 mg by mouth daily, days 1-21 of each 28-day cycle with rituximab 375 mg/m 2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 5, 7, 9 and 11 in the induction phase of the trial (n = 222). In the AUGMENT trial, 88.1% of patients completed at least 6 cycles of lenalidomide capsules/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6 cycles of lenalidomide capsules/rituximab, and 30.6% of patients completed 12 cycles. Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White. Fatal adverse reactions occurred in 6 patients (1.5%) receiving lenalidomide capsules/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving lenalidomide capsules/rituximab in AUGMENT and 29% in MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the lenalidomide capsules/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of lenalidomide capsules or rituximab due to an adverse reaction occurred in 14.6% of patients in the lenalidomide capsules/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of lenalidomide capsules or rituximab was neutropenia (4.8%). The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%). Table 12: All Grade Adverse Reactions (≥ 5%) or Grade 3/4 Adverse Reactions (≥ 1%) in Patients with FL and MZL with a Difference Between Arms of > 1% When Compared to Control Arm in AUGMENT Trial Note: Adverse reactions are coded to body system/adverse reaction using MedDRA 21. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse reaction. All Adverse Reactions All treatment-emergent AEs in at least 5% of patients in the lenalidomide capsules + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). Grade 3/4 Adverse Reactions All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the lenalidomide capsules + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). Body System Adverse Reaction Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]): Lenalidomide Capsules + Rituximab Arm (N = 176) n (%) Rituximab + Placebo (Control Arm) (N = 180) n (%) Lenalidomide Capsules + Rituximab Arm (N = 176) n (%) Rituximab + Placebo (Control Arm) (N = 180) n (%) Infections and infestations Upper respiratory tract infection 32 (18) 23 (13) 2 (1.1) 4 (2.2) Influenza - 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). 17 (10) 8 (4.4) 1 (< 1) 0 (0) Pneumonia All serious treatment-emergent AEs in at least 1% of patients in the lenalidomide capsules + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). Serious ADR reported. 13 (7) 6 (3.3) 6 (3.4) 4 (2.2) Sinusitis 13 (7) 5 (2.8) 0 (0) 0 (0) Urinary tract infection 13 (7) 7 (3.9) 1 (< 1) 1 (< 1) Bronchitis 8 (4.5) 6 (3.3) 2 (1.1) 0 (0) Gastroenteritis 6 (3.4) 4 (2.2) 2 (1.1) 0 (0) Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumor flare 19 (11) 1 (< 1) 1 (< 1) 0 (0) Blood and lymphatic disorders Neutropenia 102 (58) 40 (22) 88 (50) 23 (13) Leukopenia 36 (20) 17 (9) 12 (7) 3 (1.7) Anemia 28 (16) 8 (4.4) 8 (4.5) 1 (< 1) Thrombocytopenia 26 (15) 8 (4.4) 4 (2.3) 2 (1.1) Lymphopenia 8 (4.5) 14 (8) 5 (2.8) 2 (1.1) Febrile Neutropenia 5 (2.8) 1 (< 1) 5 (2.8) 1 (< 1) Metabolism and nutrition disorders Decreased Appetite 23 (13) 11 (6) 2 (1.1) 0 (0) Hypokalemia 14 (8) 5 (2.8) 4 (2.3) 0 (0) Hyperuricemia 10 (6) 8 (4.4) 1 (< 1) 1 (< 1) Nervous system disorders Headache 26 (15) 17 (9) 1 (< 1) 0 (0) Dizziness 15 (9) 9 (5) 0 (0) 0 (0) Vascular disorders Hypotension 9 (5) 1 (< 1) 1 (< 1) 0 (0) Thromboembolic events “Thromboembolic events” combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis. 8 (4.5) 2 (1.1) 4 (2.3) 2 (1.1) Respiratory, thoracic and mediastinal disorders Cough “Cough” combined AE term includes the following PTs: cough and productive cough. 43 (24) 35 (19) 1 (< 1) 0 (0) Dyspnea 19 (11) 8 (4.4) 2 (1.1) 1 (< 1) Oropharyngeal pain 10 (6) 8 (4.4) 0 (0) 0 (0) Pulmonary Embolism 4 (2.3) 1 (< 1) 4 (2.3) 1 (< 1) Chronic obstructive pulmonary disease 3 (1.7) 0 (0) 2 (1.1) 0 (0) Respiratory failure 2 (1.1) 1 (< 1) 2 (1.1) 0 (0) Gastrointestinal disorders Diarrhea 55 (31) 41 (23) 5 (2.8) 0 (0) Constipation 46 (26) 25 (14) 0 (0) 0 (0) Abdominal pain “Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper. 32 (18) 20 (11) 2 (1.1) 0 (0) Vomiting 17 (10) 13 (7) 0 (0) 0 (0) Dyspepsia 16 (9) 5 (2.8) 0 (0) 0 (0) Stomatitis 9 (5) 7 (3.9) 0 (0) 0 (0) Skin and subcutaneous tissue disorders Rash “Rash” combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and rash generalized. 39 (22) 14 (8) 5 (2.8) 2 (1.1) Pruritus “Pruritus” combined AE term includes the following PTs: pruritus, pruritus generalized, rash pruritic, and pruritus allergic. 36 (20) 9 (5) 2 (1.1) 0 (0) Dry skin 9 (5) 6 (3.3) 0 (0) 0 (0) Dermatitis acneiform 8 (4.5) 0 (0) 2 (1.1) 0 (0) Musculoskeletal and connective tissue disorders Muscle Spasms 23 (13) 9 (5) 1 (< 1) 1 (< 1) Pain in Extremity 8 (4.5) 9 (5) 2 (1) 0 (0) Renal disorders Acute Kidney Injury - adverse reactions in which at least one resulted in a fatal outcome. 3 (1.7) 0 (0) 2 (1.1) 0 (0) Cardiac disorders Supraventricular tachycardia 2 (1.1) 0 (0) 2 (1.1) 0 (0) General disorders and administration site conditions Fatigue 38 (22) 33 (18) 2 (1.1) 1 (< 1) Pyrexia 37 (21) 27 (15) 1 (< 1) 3 (1.7) Asthenia 24 (14) 19 (11) 2 (1.1) 1 (< 1) Edema Peripheral 23 (13) 16 (9) 0 (0) 0 (0) Chills 14 (8) 8 (4.4) 0 (0) 0 (0) Malaise 13 (7) 10 (6) 0 (0) 0 (0) Influenza like illness 9 (5) 7 (3.9) 0 (0) 0 (0) Psychiatric disorders Insomnia 14 (8) 11 (6) 0 (0) 0 (0) Investigations Alanine Aminotransferase Increased 18 (10) 15 (8) 3 (1.7) 1 (< 1) WBC count decreased 16 (9) 13 (7) 5 (2.8) 2 (1.1) Lymphocyte count decreased 12 (7) 12 (7) 6 (3.4) 2 (1.1) Blood bilirubin increased 10 (6) 0 (0) 0 (0) 0 (0) Weight Decreased 12 (7) 2 (1.1) 0 (0) 0 (0) 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide postmarketing experience with lenalidomide capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.8 , 5.9 , 5.10 , 5.11 , and 5.13) ] . Endocrine Disorders: Hypothyroidism, hyperthyroidism Hepatobiliary Disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests Immune System Disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection Infections and Infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML) Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): Tumor lysis syndrome, tumor flare reaction Respiratory, Thoracic and Mediastinal Disorders: Pneumonitis Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)