LENALIDOMIDE Dailymed

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 Hetero Labs Limited at 1-866-495-1995 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 Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide with low dose examethasone (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 were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was 7 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 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*

Body System Adverse Reaction	All Adverse Reactions a						Grade 3/4 Adverse Reactions b
	Rd Continuous (N = 532)		Rd18 (N = 540)		MPT (N = 541)		Rd Continuous (N = 532)		Rd18 (N = 540)	MPT (N = 541)
General disorders and administration site conditions
Fatigue %	173 (33)		177 (33)		154 (28)		39 ( 7)		46 ( 9)	31 ( 6)
Asthenia	150 (28)		123 (23)		124 (23)		41 ( 8)		33 ( 6)	32 ( 6)
Pyrexia c	114 (21)		102 (19)		76 (14)		13 ( 2)		7 ( 1)	7 ( 1)
Non-cardiac chest pain f	29 ( 5)		31 ( 6)		18 ( 3)		<1%		< 1%	< 1%
Gastrointestinal disorders
Diarrhea	242 (45)		208 (39)		89 (16)		21 ( 4)		18 ( 3)	8 ( 1)
Abdominal pain % f	109 (20)		78 (14)		60 (11)		7 ( 1)		9 ( 2)	< 1%
Dyspepsia f	57 (11)		28 ( 5)		36 ( 7)		<1%		< 1%	0 ( 0)
Musculoskeletal and connective tissue disorders
Back pain c	170 (32)		145 (27)		116 (21)		37 ( 7)		34 ( 6)	28 ( 5)
Muscle spasms f	109 (20)		102 (19)		61 (11)		< 1%		< 1%	< 1%
Arthralgia f	101 (19)		71 (13)		66 (12)		9 ( 2)		8 ( 1)	8 ( 1)
Bone pain f	87 (16)		77 (14)		62 (11)		16 ( 3)		15 ( 3)	14 ( 3)
Pain in extremity f	79 (15)		66 (12)		61 (11)		8 ( 2)		8 ( 1)	7 ( 1)
Body System Adverse Reaction		All Adverse Reactions a						Grade 3/4 Adverse Reactions b
		Rd Continuous (N = 532)		Rd18 (N = 540)		MPT (N = 541)		Rd Continuous (N = 532)	Rd18 (N = 540)		MPT (N = 541)
Musculoskeletal pain f		67 (13)		59 (11)		36 ( 7)		< 1%	< 1%		< 1%
Musculoskeletal chest pain f		60 (11)		51 ( 9)		39 ( 7)		6 ( 1)	< 1%		< 1%
Muscular weakness f		43 ( 8)		35 ( 6)		29 ( 5)		< 1%	8 ( 1)		< 1%
Neck pain f		40 ( 8)		19 ( 4)		10 ( 2)		< 1%	< 1%		< 1%
Infections and infestations
Bronchitis c		90 (17)		59 (11)		43 ( 8)		9 ( 2)	6 ( 1)		< 1%
Nasopharyngitis f		80 (15)		54 (10)		33 ( 6)		0 ( 0)	0 ( 0)		0 ( 0)
Urinary tract infection f		76 (14)		63 (12)		41 ( 8)		8 ( 2)	8 ( 1)		< 1%
Upper respiratory tract infection c% f		69 (13)		53 ( 10)		31 ( 6)		< 1%	8 ( 1)		< 1%
Pneumonia c@		93 (17)		87 (16)		56 (10)		60 (11)	57 (11)		41 ( 8)
Respiratory tract infection %		35 ( 7)		25 ( 5)		21 ( 4)		7 ( 1)	< 1%		< 1%
Influenza f		33 ( 6)		23 ( 4)		15 ( 3)		< 1%	< 1%		0 ( 0)
Gastroenteritis f		32 ( 6)		17 ( 3)		13 ( 2)		0 ( 0)	< 1%		< 1%
Lower respiratory tract infection		29 ( 5)		14 ( 3)		16 ( 3)		10 ( 2)	< 1%		< 1%
Rhinitis f		29 ( 5)		24 ( 4)		14 ( 3)		0 ( 0)	0 ( 0)		0 ( 0)
Cellulitis c		< 5%		< 5%		< 5%		8 ( 2)	< 1%		< 1%
Sepsis c@		33 ( 6)		26 ( 5)		18 ( 3)		26 ( 5)	20 ( 4)		13 ( 2)
Nervous system disorders
Headache f		75 (14)		52 ( 10)		56 (10)		< 1%	< 1%		< 1%
Dysgeusia f		39 ( 7)		45 ( 8)		22 ( 4)		< 1%	0 ( 0.0)		< 1%
Blood and lymphatic system disorders d
Anemia		233 (44)		193 (36)		229 (42)		97 (18)	85 (16)		102 (19)
Neutropenia		186 (35)		178 (33)		328 (61)		148 (28)	143 (26)		243 (45)
Thrombocytopenia		104 (20)		100 (19)		135 (25)		44 ( 8)	43 ( 8)		60 (11)
Febrile neutropenia		7 ( 1)		17 ( 3)		15 ( 3)		6 ( 1)	16 ( 3)		14 ( 3)
Pancytopenia		< 1%		6 ( 1)		7 ( 1)		< 1%	< 1%		< 1%
Respiratory, thoracic and mediastinal disorders
Cough f		121 (23)		94 (17)		68 (13)		< 1%	< 1%		< 1%
Dyspnea c,e		117 (22)		89 (16)		113 (21)		30 ( 6)	22 ( 4)		18 ( 3)
Epistaxis f		32 ( 6)		31 ( 6)		17 ( 3)		< 1%	< 1%		0 ( 0)
Oropharyngeal pain f		30 ( 6)		22 ( 4)		14 ( 3)		0 ( 0)	0 ( 0)		0 ( 0)
Dyspnea exertional e		27 ( 5)		29 ( 5)		< 5%		6 ( 1)	< 1%		0 ( 0)
Metabolism and nutrition disorders
Decreased appetite		123 (23)		115 (21)		72 (13)		14 ( 3)	7 ( 1)		< 1%
Hypokalemia %		91 (17)		62 (11)		38 ( 7)		35 ( 7)	20 ( 4)		11 ( 2)
Hyperglycemia		62 (12)		52 ( 10)		19 ( 4)		28 ( 5)	23 ( 4)		9 ( 2)
Hypocalcemia		57 (11)		56 (10)		31 ( 6)		23 ( 4)	19 ( 4)		8 ( 1)
Dehydration %		25 ( 5)		29 ( 5)		17 ( 3)		8 ( 2)	13 ( 2)		9 ( 2)
Gout e		< 5%		< 5%		< 5%		8 ( 2)	0 ( 0)		0 ( 0)
Diabetes mellitus % e		< 5%		< 5%		< 5%		8 ( 2)	< 1%		< 1%
Hypophosphatemia e		< 5%		< 5%		< 5%		7 ( 1)	< 1%		< 1%
Hyponatremia % e		< 5%		< 5%		< 5%		7 ( 1)	13 ( 2)		6 ( 1)
Skin and subcutaneous tissue disorders
Rash		139 (26)		151 (28)		105 (19)		39 ( 7)	38 ( 7)		33 ( 6)
Pruritus f		47 ( 9)		49 ( 9)		24 ( 4)		< 1%	< 1%		< 1%
Psychiatric disorders
Insomnia		147 (28)		127 (24)		53 ( 10)		< 1%	6 ( 1)		0 ( 0)
Depression		58 (11)		46 ( 9)		30 ( 6)		10 ( 2)	< 1%		< 1%
Body System Adverse Reaction		All Adverse Reactions a						Grade 3/4 Adverse Reactions b
		Rd Continuous (N = 532)		Rd18 (N = 540)		MPT (N = 541)		Rd Continuous (N = 532)	Rd18 (N = 540)		MPT (N = 541)
Vascular disorders
Deep vein thrombosis c%		55 (10)		39 ( 7)		22 ( 4)		30 ( 6)	20 ( 4)		15 ( 3)
Hypotension c%		51 ( 10)		35 ( 6)		36 ( 7)		11 ( 2)	8 ( 1)		6 ( 1)
Injury, Poisoning, and Procedural Complications
Fall f		43 ( 8)		25 ( 5)		25 ( 5)		< 1%	6 ( 1)		6 ( 1)
Contusion f		33 ( 6)		24 ( 4)		15 ( 3)		< 1%	< 1%		0 ( 0)
Eye disorders
Cataract		73 (14)		31 ( 6)		< 1%		31 ( 6)	14 ( 3)		< 1%
Cataract subcapsular e		< 5%		< 5%		< 5%		7 ( 1)	0 ( 0)		0 ( 0)
Investigations
Weight decreased		72 (14)		78 (14)		48 ( 9)		11 ( 2)	< 1%		< 1%
Cardiac disorders
Atrial fibrillation c		37 ( 7)		25 ( 5)		25 ( 5)		13 ( 2)	9 ( 2)		6 ( 1)
Myocardial infarction (including acute) c ,e		< 5%		< 5%		< 5%		10 ( 2)	< 1%		< 1%
Renal and Urinary disorders
Renal failure (including acute) c@,f		49 ( 9)		54 (10)		37 ( 7)		28 ( 5)	33 ( 6)		29 ( 5)
Neoplasms benign, malignant and unspecified (Including cysts and polyps)
Squamous cell carcinoma c e		< 5%		< 5%		< 5%		8 ( 2)	< 1%		0 ( 0)
Basal cell carcinoma c e,f		< 5%		< 5%		< 5%		< 1%	< 1%		0 ( 0)

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. ^aAll 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. ^bAll 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. ^cSerious 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 rms compared to the MPT Arm. ^dPreferred 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. ^eFootnote “a” not applicable. ^fFootnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

*Adverse reactions included in combined adverse reaction terms: Abdominal Pain:Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias:Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis:Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash:Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis:Deep vein thrombosis, venous thrombosis limb, venous thrombosis Newly Diagnosed MM - Lenalidomide Maintenance Therapy Following Auto-HSCT: Data were evaluated from 1018 patients in two randomized trials who received at least one dose of lenalidomide 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for lenalidomide 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 arm were still on treatment and none of the patients in the Maintenance Study 2 lenalidomide arm were still on treatment at the same cut-off date. Grade 3 or 4 reactions (more than 20% in the lenalidomide arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the lenalidomide arm. For lenalidomide, 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 were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of lenalidomide 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 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 Vs Placebo Arms*



Note:Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.

^aAll treatment-emergent AEs in at least 5% of patients in the lenalidomide Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. ^bAll grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the lenalidomide Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group.

^cAll serious treatment-emergent AEs in at least 1% of patients in the lenalidomide Maintenance group and at least 1% higher frequency (%) than the Placebo

Maintenance group. ^dFootnote “a” not applicable for either study ^eFootnote “b” not applicable for either study @ -ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered uled *Adverse Reactions for combined ADR terms(based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): PneumoniasBronchopneumonia, 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

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 /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 a 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 a dose reduction, 50% in the LENALIDOMIDE/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 /dexamethasone compared to placebo/dexamethasone. Tables 6, 7, and 8 summarize the adverse reactions reported for lenalidomide/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 /dexamethasone and Placebo/dexamethasone Groups



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 /dexamethasone and Placebo/dexamethasone groups

Body System Adverse Reaction	Lenalidomide /Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia %	118 (33)	12 ( 3)
Thrombocytopenia @	43 (12)	22 ( 6)
Anemia @	35 ( 10)	20 ( 6)
Leukopenia	14 ( 4)	< 1%
Lymphopenia	10 ( 3)	4 ( 1)
Febrile neutropenia %	8 ( 2)	0 ( 0)
General disorders and administration site conditions
Fatigue	23 ( 7)	17 ( 5)
Vascular disorders
Deep vein thrombosis %	29 ( 8)	12 ( 3)
Infections and infestations
Pneumonia @	30 ( 8)	19 ( 5)
Urinary tract infection	5 ( 1)	< 1%
Metabolism and nutrition disorders
Hypokalemia	17 ( 5)	5 ( 1)
Hypocalcemia	13 ( 4)	6 ( 2)
Hypophosphatemia	9 ( 3)	0 ( 0)
Respiratory, thoracic and mediastinal disorders
Body System Adverse Reaction	Lenalidomide /Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
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/dexamethasone and Placebo/dexamethasone Groups

Body System Adverse Reaction	Lenalidomide /Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Febrile neutropenia %	6 ( 2)	0 ( 0)
Vascular disorders
Deep vein thrombosis %	26 ( 7)	11 ( 3)
Infections and infestations
Pneumonia @	33 ( 9)	21 ( 6)
Respiratory, thoracic, and mediastinal disorders
Pulmonary embolism @	13 ( 4)	< 1%
Cardiac disorders
Atrial fibrillation @	11 ( 3)	< 1%
Cardiac failure congestive @	5 ( 1)	0 ( 0)
Nervous system disorders
Cerebrovascular accident @	7 ( 2)	< 1%
Gastrointestinal disorders
Diarrhea @	6 ( 2)	< 1%
Musculoskeletal and connective tissue disorders
Bone pain	4 ( 1)	0 ( 0)

Median duration of exposure among patients treated with 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. 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 /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 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 /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 /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 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 /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 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 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. 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 leanlidomide 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. 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 Treated Patients in del 5q MDS Clinical Study

	10 mg Overall
Body System Adverse Reaction a	(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)
		10 mg Overall
Body System Adverse Reaction a		(N=148)
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 DisordersNasopharyngitis		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 DisordersHypokalemia		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)

^a Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are uled 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. Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions 1 Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

	10 mg
Adverse Reactions 2	(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)

¹Adverse 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. ²Adverse 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. 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 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, Enterobactersepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiellasepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcalinfection, 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. 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. 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

Body System Adverse Reaction	All Adverse Reactions 1 (N=134) n (%)	Grade 3/4 Adverse Reactions 2(N=134) n (%)
General disorders and administration site conditions
Fatigue	45 (34)	9 (7)
Pyrexia $	31 (23)	3 (2)
Edema peripheral	21 (16)	0
Asthenia $	19 (14)	4 (3)
General physical health deterioration	3 (2)	2 (1)
Gastrointestinal disorders
Diarrhea $	42 (31)	8 (6)
Nausea $	40 (30)	1 (<1)
Constipation	21 (16)	1 (<1)
Vomiting $	16 (12)	1 (<1)
Abdominal pain $	13 (10)	5 ( 4)
Musculoskeletal and connective tissue disorders
Back pain	18 (13)	2 (1)
Muscle spasms	17 (13)	1 (<1)
Arthralgia	11 (8)	2 (1)
Muscular weakness $	8 (6)	2 ( 1)
Respiratory, thoracic and mediastinal disorders
Cough	38 (28)	1 (<1)
Body System Adverse Reaction	All Adverse Reactions [1] (N=134) n (%)	Grade 3/4 Adverse Reactions [2](N=134) n (%)
Dyspnea $	24 (18)	8 (6)
Pleural Effusion	10 (7)	2 (1)
Hypoxia	3 (2)	2 (1)
Pulmonary embolism	3 (2)	2 ( 1)
Respiratory distress $	2 (1)	2 (1)
Oropharyngeal pain	13 (10)	0
Infections and infestations
Pneumonia @ $	19 (14)	12 (9)
Upper respiratory tract infection	17 (13)	0
Cellulitis $	3 (2)	2 (1)
Bacteremia $	2 (1)	2 (1)
Staphylococcal sepsis $	2 (1)	2 (1)
Urinary tract infection $	5 (4)	2 (1)
Skin and subcutaneous tissue disorders
Rash +	30 (22)	2 (1)
Pruritus	23 (17)	1 (<1)
Blood and lymphatic system disorders
Neutropenia	65 (49)	58 (43)
Thrombocytopenia % $	48 (36)	37 (28)
Anemia $	41 (31)	15 (11)
Leukopenia $	20 (15)	9 (7)
Lymphopenia	10 ( 7)	5 (4)
Febrile neutropenia $	8 (6)	8 (6)

^1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects. ²-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects. $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects. @ - Adverse reactions where at least one resulted in a fatal outcome. % - Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases). # - All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered uled. + - All adverse reactions under HLT of Rash will be considered uled.

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 monotherapy for mantle cell lymphoma. Cardiac disorder:Cardiac failure Ear and labyrinth disorders:Vertigo General disorders and administration site conditions:Chills Infections and infestations:Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes Musculoskeletal and connective tissue disorders:Pain in extremity Nervous system disorders:Dysgeusia, headache, neuropathy peripheral, lethargy Psychiatric disorders:Insomnia Skin and subcutaneous tissue disorders:Dry skin, night sweats

The following serious adverse reactions not described above and reported in 2 or more patients treated with lenalidomide monotherapy for mantle cell lymphoma. Blood and lymphatic system disorders:Neutropenia Cardiac disorder:Myocardial infarction (including acute MI), supraventricular tachycardia Infections and infestations:Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (including cysts and polyps):Basal cell carcinoma Respiratory, thoracic, and mediastinal disorders:Chronic obstructive pulmonary disease, pulmonary embolism Follicular Lymphoma or Marginal Zone Lymphoma The safety of lenalidomide / 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/mm3 and platelets≥ 75,000/mm ³(unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥8g/dL, AST and ALT ≤ 3x ULN (unless documented liver involvement with lymphoma, and creatinine clearance of ≥ 30mL/min. Subjects with active HIV, hepatitis B or C were not eligible. In the AUGMENT trial, patients received lenalidomide 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m ²weekly (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 ²weekly (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 20 mg by mouth daily, days 1-21 of each 28 day cycle with rituximab 375 mg/m ²weekly (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 /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 /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 /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 /rituximab in AUGMENT and 29% in MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the lenalidomide /rituximab arm was febrile neutropenia (3%). Permanent discontinuation of lenalidomide or rituximab due to an adverse reaction occurred in 14.6% of patients in the lenalidomide /rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of lenalidomide 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

Body System Adverse Reaction*	All Adverse Reactions 1			Grade 3 / 4 Adverse Reactions 2
	Lenalidomide + Rituximab Arm (N=176)n (%)	Rituximab + Placebo (Control Arm) (N=180)n (%)		Lenalidomide + Rituximab Arm (N=176) n (%)		Rituximab + Placebo (Control Arm) (N=180)n (%)
Infections and infestations
Upper respiratory tract infection	32 (18)	23 (13)		2 (1.1)		4 (2.2)
Influenza %	17 (10)	8 (4.4)		1 (< 1)		0 (0)
Pneumonia 3,$,%	13 (7)	6 (3.3)		6 (3.4)		4 (2.2)
Sinusitis	13 (7)	5 (2.8)		0 (0)		0 (0)
Urinary tract infection $	13 (7)	7 (3.9)		1 (< 1)		1 (< 1)
Bronchitis	8 (4.5)	6 (3.3)		2 (1.1)		0 (0)
Gastroenteritis $	6 (3.4)	4 (2.2)		2 (1.1)		0 (0)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Tumor flare $	19 (11)	1 (< 1)		1 (< 1)		0 (0)
Blood and lymphatic disorders
Neutropenia 3,$, %	102 (58)	40 (22)		88 (50)		23 (13)
Body System Adverse Reaction*	All Adverse Reactions 1				Grade 3 / 4 Adverse Reactions 2
	Lenalidomide + Rituximab Arm (N=176)n (%)		Rituximab + Placebo (Control Arm) (N=180)n (%)		Lenalidomide + Rituximab Arm (N=176) n (%)		Rituximab + Placebo (Control Arm) (N=180)n (%)
Leukopenia $,%	36 (20)		17 (9)		12 (7)		3 (1.7)
Anemia 3,$	28 (16)		8 (4.4)		8 (4.5)		1 (< 1)
Thrombocytopenia 3,$,%	26 (15)		8 (4.4)		4 (2.3)		2 (1.1)
Lymphopenia	8 (4.5)		14 (8)		5 (2.8)		2 (1.1)
Febrile Neutropenia 3,$,%	5 (2.8)		1 (< 1)		5 (2.8)		1 (< 1)
Metabolism and nutrition disorders
Decreased Appetite	23 (13)		11 (6)		2 (1.1)		0 (0)
Hypokalemia %	14 (8)		5 (2.8)		4 (2.3)		0 (0)
Hyperuricemia	10 (6)		8 (4.4)		1 (< 1)		1 (< 1)
Nervous system disorders
Headache	26 (15)		17 (9)		1 (< 1)		0 (0)
Dizziness	15 (9)		9 (5)		0 (0)		0 (0)
Vascular disorders
Hypotension %	9 (5)		1 (< 1)		1 (< 1)		0 (0)
Thromboembolic events a,$	8 (4.5)		2 (1.1)		4 (2.3)		2 (1.1)
Respiratory, thoracic and mediastinal disorders
Cough b	43 (24)		35 (19)		1 (< 1)		0 (0)
Dyspnea $	19 (11)		8 (4.4)		2 (1.1)		1 (< 1)
Oropharyngeal pain	10 (6)		8 (4.4)		0 (0)		0 (0)
Pulmonary Embolism 3,$	4 (2.3)		1 (< 1)		4 (2.3)		1 (< 1)
Chronic obstructive pulmonary disease $	3 (1.7)		0 (0)		2 (1.1)		0 (0)
Respiratory failure 3,$	2 (1.1)		1 (< 1)		2 (1.1)		0 (0)
Gastrointestinal disorders
Diarrhea $,%	55 (31)		41 (23)		5 (2.8)		0 (0)
Constipation	46 (26)		25 (14)		0 (0)		0 (0)
Abdominal pain c ,$	32 (18)		20 (11)		2 (1.1)		0 (0)
Vomiting $	17 (10)		13 (7)		0 (0)		0 (0)
Dyspepsia	16 (9)		5 (2.8)		0 (0)		0 (0)
Stomatitis	9 (5)		7 (3.9)		0 (0)		0 (0)
Skin and subcutaneous tissue disorders
Rash $,d	39 (22)		14 (8)		5 (2.8)		2 (1.1)
Pruritus $,e	36 (20)		9 (5)		2 (1.1)		0 (0)
Dry skin	9 (5)		6 (3.3)		0 (0)		0 (0)
Dermatitis acneiform	8 (4.5)		0 (0)		2 (1.1)		0 (0)
Musculoskeletal and connective tissue disorders
Muscle Spasms	23 (13)		9 (5)		1 (< 1)		1 (< 1)
Pain in Extremity $	8 (4.5)		9 (5)		2 (1)		0 (0)
Renal disorders
Acute Kidney Injury 3,$,@,%	3 (1.7)		0 (0)		2 (1.1)		0 (0)
Body System Adverse Reaction*	All Adverse Reactions 1				Grade 3 / 4 Adverse Reactions 2
	Lenalidomide + Rituximab Arm (N=176)n (%)		Rituximab + Placebo (Control Arm) (N=180)n (%)		Lenalidomide + Rituximab Arm (N=176) n (%)		Rituximab + Placebo (Control Arm) (N=180)n (%)
Cardiac disorders
Supraventricular tachycardia 3,$	2 (1.1)		0 (0)		2 (1.1)		0 (0)
General disorders and administration site conditions
Fatigue	38 (22)		33 (18)		2 (1.1)		1 (< 1)
Pyrexia 3,$	37 (21)		27 (15)		1 (< 1)		3 (1.7)
Asthenia $,%	24 (14)		19 (11)		2 (1.1)		1 (< 1)
Edema Peripheral $	23 (13)		16 (9)		0 (0)		0 (0)
Chills	14 (8)		8 (4.4)		0 (0)		0 (0)
Malaise	13 (7)		10 (6)		0 (0)		0 (0)
Influenza like illness	9 (5)		7 (3.9)		0 (0)		0 (0)
Psychiatric disorders
Insomnia	14 (8)		11 (6)		0 (0)		0 (0)
Investigations
Alanine Aminotransferase Increased	18 (10)		15 (8)		3 (1.7)		1 (< 1)
WBC count decreased	16 (9)		13 (7)		5 (2.8)		2 (1.1)
Lymphocyte count decreased	12 (7)		12 (7)		6 (3.4)		2 (1.1)
Blood bilirubin increased	10 (6)		0 (0)		0 (0)		0 (0)
Weight Decreased	12 (7)		2 (1.1)		0 (0)		0 (0)

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. ¹All treatment-emergent AEs in at least 5% of patients in the lenalidomide + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). ²All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the lenalidomide + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). ³All serious treatment-emergent AEs in at least 1% of patients in the lenalidomide + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). $ Serious ADR reported. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]): ^a“Thromboembolic events” combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis. ^b“Cough” combined AE term includes the following PTs: cough and productive cough. ^c“Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper. ^d“Rash” combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and rash generalized. ^e“Pruritus” combined AE term includes the following PTs: pruritus, pruritus generalized, rash pruritic, and pruritus allergic.

6.2 Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with lenalidomide. 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 ( 5.8to 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)