Revlimid (lenalidomide 10 mg) Dailymed

6 Adverse Reactions

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:

• oEmbryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]
• oHematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)]
• oVenous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]
• oIncreased Mortality in Patients with CLL [see Warnings and Precautions (5.5)]
• oSecond Primary Malignancies [see Warnings and Precautions (5.6)]
• oIncreased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7)]
• oHepatotoxicity [see Warnings and Precautions (5.8)]
• oSevere Cutaneous Reactions[see Warnings and Precautions (5.9)]
• oTumor Lysis Syndrome [see Warnings and Precautions (5.10)]
• oTumor Flare Reactions [see Warnings and Precautions (5.11)]
• oImpaired Stem Cell Mobilization [see Warnings and Precautions (5.12)]
• oThyroid Disorders [see Warnings and Precautions (5.13)]
• oEarly Mortality in Patients with MCL [see Warnings and Precautions (5.14)]
• oHypersensitivity [see Warnings and Precautions (5.15)]

• •MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor (6.1).
• •MDS: Most common adverse reactions (>15%) include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis (6.1).
• •Non-Hodgkin's Lymphoma (NHL: MCL, FL or MZL): Most common adverse reactions (≥15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed MM – REVLIMID Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms*

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable. f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse reactions included in combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis
Body System Adverse Reaction	All Adverse Reactionsa			Grade 3/4 Adverse Reactionsb
	Rd Continuous (N = 532)	Rd18 (N = 540)	MPT (N = 541)	Rd Continuous (N = 532)	Rd18 (N = 540)	MPT (N = 541)
General disorders and administration site conditions
Fatigue%	173 (33)	177 (33)	154 (28)	39 ( 7)	46 ( 9)	31 ( 6)
Asthenia	150 (28)	123 (23)	124 (23)	41 ( 8)	33 ( 6)	32 ( 6)
Pyrexiac	114 (21)	102 (19)	76 (14)	13 ( 2)	7 ( 1)	7 ( 1)
Non-cardiac chest 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 painc	170 (32)	145 (27)	116 (21)	37 ( 7)	34 ( 6)	28 ( 5)
Muscle spasms f	109 (20)	102 (19)	61 (11)	< 1%	< 1%	< 1%
Arthralgia f	101 (19)	71 (13)	66 (12)	9 ( 2)	8 ( 1)	8 ( 1)
Bone pain f	87 (16)	77 (14)	62 (11)	16 ( 3)	15 ( 3)	14 ( 3)
Pain in extremity f	79 (15)	66 (12)	61 (11)	8 ( 2)	8 ( 1)	7 ( 1)
Musculoskeletal pain f	67 (13)	59 (11)	36 ( 7)	< 1%	< 1%	< 1%
Musculoskeletal chest pain f	60 (11)	51 ( 9)	39 ( 7)	6 ( 1)	< 1%	< 1%
Muscular weakness f	43 ( 8)	35 ( 6)	29 ( 5)	< 1%	8 ( 1)	< 1%
Neck pain f	40 ( 8)	19 ( 4)	10 ( 2)	< 1%	< 1%	< 1%
Infections and infestations
Bronchitisc	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 infectionc% f	69 (13)	53 ( 10)	31 ( 6)	< 1%	8 ( 1)	< 1%
Pneumoniac@	93 (17)	87 (16)	56 (10)	60 (11)	57 (11)	41 ( 8)
Respiratory tract infection%	35 ( 7)	25 ( 5)	21 ( 4)	7 ( 1)	< 1%	< 1%
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)
Cellulitisc	< 5%	< 5%	< 5%	8 ( 2)	< 1%	< 1%
Sepsisc@	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 disordersd
Anemia	233 (44)	193 (36)	229 (42)	97 (18)	85 (16)	102 (19)
Neutropenia	186 (35)	178 (33)	328 (61)	148 (28)	143 (26)	243 (45)
Thrombocytopenia	104 (20)	100 (19)	135 (25)	44 ( 8)	43 ( 8)	60 (11)
Febrile neutropenia	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%
Dyspneac,e	117 (22)	89 (16)	113 (21)	30 ( 6)	22 ( 4)	18 ( 3)
Epistaxis f	32 ( 6)	31 ( 6)	17 ( 3)	< 1%	< 1%	0 ( 0)
Oropharyngeal pain f	30 ( 6)	22 ( 4)	14 ( 3)	0 ( 0)	0 ( 0)	0 ( 0)
Dyspnea exertional e	27 ( 5)	29 ( 5)	< 5%	6 ( 1)	< 1%	0 ( 0)
Metabolism and nutrition disorders
Decreased appetite	123 (23)	115 (21)	72 (13)	14 ( 3)	7 ( 1)	< 1%
Hypokalemia%	91 (17)	62 (11)	38 ( 7)	35 ( 7)	20 ( 4)	11 ( 2)
Hyperglycemia	62 (12)	52 (10)	19 ( 4)	28 ( 5)	23 ( 4)	9 ( 2)
Hypocalcemia	57 (11)	56 (10)	31 ( 6)	23 ( 4)	19 ( 4)	8 ( 1)
Dehydration%	25 ( 5)	29 ( 5)	17 ( 3)	8 ( 2)	13 ( 2)	9 ( 2)
Gout e	< 5%	< 5%	< 5%	8 ( 2)	0 ( 0)	0 ( 0)
Diabetes mellitus% e	< 5%	< 5%	< 5%	8 ( 2)	< 1%	< 1%
Hypophosphatemia e	< 5%	< 5%	< 5%	7 ( 1)	< 1%	< 1%
Hyponatremia% e	< 5%	< 5%	< 5%	7 ( 1)	13 ( 2)	6 ( 1)
Skin and subcutaneous tissue disorders
Rash	139 (26)	151 (28)	105 (19)	39 ( 7)	38 ( 7)	33 ( 6)
Pruritus f	47 ( 9)	49 ( 9)	24 ( 4)	< 1%	< 1%	< 1%
Psychiatric disorders
Insomnia	147 (28)	127 (24)	53 ( 10)	< 1%	6 ( 1)	0 ( 0)
Depression	58 (11)	46 ( 9)	30 ( 6)	10 ( 2)	< 1%	< 1%
Vascular disorders
Deep vein thrombosisc%	55 (10)	39 ( 7)	22 ( 4)	30 ( 6)	20 ( 4)	15 ( 3)
Hypotensionc%	51 (10)	35 ( 6)	36 ( 7)	11 ( 2)	8 ( 1)	6 ( 1)
Injury, Poisoning, and Procedural Complications
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 fibrillationc	37 ( 7)	25 ( 5)	25 ( 5)	13 ( 2)	9 ( 2)	6 ( 1)
Myocardial infarction (including acute)c ,e	< 5%	< 5%	< 5%	10 ( 2)	< 1%	< 1%
Renal and Urinary disorders
Renal failure (including acute)c@,f	49 ( 9)	54 (10)	37 ( 7)	28 ( 5)	33 ( 6)	29 ( 5)
Neoplasms benign, malignant and unspecified (Including cysts and polyps)
Squamous cell carcinomac e	< 5%	< 5%	< 5%	8 ( 2)	< 1%	0 ( 0)
Basal cell carcinomac e,f	< 5%	< 5%	< 5%	< 1%	< 1%	0 ( 0)

Newly Diagnosed MM - REVLIMID Maintenance Therapy Following Auto-HSCT:

Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for REVLIMID treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date

The adverse reactions uled from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the REVLIMID arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.

For REVLIMID, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of REVLIMID were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2.

The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment.

Table 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms.

Table 5: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the REVLIMID Vs Placebo Arms*

Note : Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent AEs in at least 5% of patients in the REVLIMID Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. b All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. c All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study @ - ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases)# - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered uled *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): Pneumonias Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis
Body System Adverse Reaction	Maintenance Study 1				Maintenance Study 2
	All Adverse Reactions a		Grade 3/4 Adverse Reactions b		All Adverse Reactions a		Grade 3/4 Adverse Reactions b
	REVLIMID (N=224) n (%)	Placebo (N=221) n (%)	REVLIMID (N=224) n (%)	Placebo (N=221) n (%)	REVLIMID (N=293) n (%)	Placebo (N=280) n (%)	REVLIMID (N=293) n (%)	Placebo (N=280) n (%)
Blood and lymphatic system disorders
Neutropenia c %	177 ( 79)	94 ( 43)	133 ( 59)	73 ( 33)	178 ( 61)	33 ( 12)	158 ( 54)	21 ( 8)
Thrombocytopenia c %	162 ( 72)	101 ( 46)	84 ( 38)	67 ( 30)	69 ( 24)	29 ( 10)	38 ( 13)	8 ( 3)
Leukopenia c	51 ( 23)	25 ( 11)	45 ( 20)	22 ( 10)	93 ( 32)	21 ( 8)	71 ( 24)	5 ( 2)
Anemia	47 ( 21)	27 ( 12)	23 ( 10)	18 ( 8)	26 ( 9)	15 ( 5)	11 ( 4)	3 ( 1)
Lymphopenia	40 ( 18)	29 ( 13)	37 ( 17)	26 ( 12)	13 ( 4)	3 ( 1)	11 ( 4)	< 1%
Pancytopenia c d %	< 1%	0 ( 0)	0 ( 0)	0 ( 0)	12 ( 4)	< 1%	7 ( 2)	< 1%
Febrile neutropenia c	39 ( 17)	34 ( 15)	39 ( 17)	34 ( 15)	7 ( 2)	< 1%	5 ( 2)	< 1%
Infections and infestations#
Upper respiratory tract infection e	60 ( 27)	35 ( 16)	7 ( 3)	9 ( 4)	32 ( 11)	18 ( 6)	< 1%	0 ( 0)
Neutropenic infection	40 ( 18)	19 ( 9)	27 ( 12)	14 ( 6)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)
Pneumonias* c %	31 ( 14)	15 ( 7)	23 ( 10)	7 ( 3)	50 ( 17)	13 ( 5)	27 ( 9)	5 ( 2)
Bronchitis c	10 ( 4)	9 ( 4)	< 1%	5 ( 2)	139 ( 47)	104 ( 37)	4 ( 1)	< 1%
Nasopharyngitis e	5 ( 2)	< 1%	0 ( 0)	0 ( 0)	102 ( 35)	84 ( 30)	< 1%	0 ( 0)
Gastroenteritis c	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)	66 ( 23)	55 ( 20)	6 ( 2)	0 ( 0)
Rhinitis e	< 1%	0 ( 0)	0 ( 0)	0 ( 0)	44 ( 15)	19 ( 7)	0 ( 0)	0 ( 0)
Sinusitis e	8 ( 4)	3 ( 1)	0 ( 0)	0 ( 0)	41 ( 14)	26 ( 9)	0 ( 0)	< 1%
Influenza c	8 ( 4)	5 ( 2)	< 1%	< 1%	39 ( 13)	19 ( 7)	3 ( 1)	0 ( 0)
Lung infection c	21 ( 9)	< 1%	19 ( 8)	< 1%	9 ( 3)	4 ( 1)	< 1%	0 ( 0)
Lower respiratory tract infection e	13 ( 6)	5 ( 2)	6 ( 3)	4 ( 2)	4 ( 1)	4 ( 1)	0 ( 0)	< 1%
Infection c	12 ( 5)	6 ( 3)	9 ( 4)	5 ( 2)	17 ( 6)	5 ( 2)	0 ( 0)	0 ( 0)
Urinary tract infection c d e	9 ( 4)	5 ( 2)	4 ( 2)	4 ( 2)	22 ( 8)	17 ( 6)	< 1%	0 ( 0)
Lower respiratory tract infection bacterial d	6 ( 3)	< 1%	4 ( 2)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)
Bacteremia d	5 ( 2)	0 ( 0)	4 ( 2)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)
Herpes zoster c d	11 ( 5)	10 ( 5)	3 ( 1)	< 1%	29 ( 10)	25 ( 9)	6 ( 2)	< 1%
Sepsis* c d @	< 1%	< 1%	0 ( 0)	0 ( 0)	6 ( 2)	< 1%	4 ( 1)	< 1%
Gastrointestinal disorders
Diarrhea	122 ( 54)	83 ( 38)	22 ( 10)	17 ( 8)	114 ( 39)	34 ( 12)	7 ( 2)	0 ( 0)
Nausea e	33 ( 15)	22 ( 10)	16 ( 7)	10 ( 5)	31 ( 11)	28 ( 10)	0 ( 0)	0 ( 0)
Vomiting	17 ( 8)	12 ( 5)	8 ( 4)	5 ( 2)	16 ( 5)	15 ( 5)	< 1%	0 ( 0)
Constipation e	12 ( 5)	8 ( 4)	0 ( 0)	0 ( 0)	37 ( 13)	25 ( 9)	< 1%	0 ( 0)
Abdominal pain e	8 ( 4)	7 ( 3)	< 1%	4 ( 2)	31 ( 11)	15 ( 5)	< 1%	< 1%
Abdominal pain upper e	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)	20 ( 7)	12 ( 4)	< 1%	0 ( 0)
General disorders and administration site conditions
Asthenia	0 ( 0)	< 1%	0 ( 0)	0 ( 0)	87 ( 30)	53 ( 19)	10 ( 3)	< 1%
Fatigue	51 ( 23)	30 ( 14)	21 ( 9)	9 ( 4)	31 ( 11)	15 ( 5)	3 ( 1)	0 ( 0)
Pyrexia e	17 ( 8)	10 ( 5)	< 1%	< 1%	60 ( 20)	26 ( 9)	< 1%	0 ( 0)
Skin and subcutaneous tissue disorders
Dry skin e	9 ( 4)	4 ( 2)	0 ( 0)	0 ( 0)	31 ( 11)	21 ( 8)	0 ( 0)	0 ( 0)
Rash	71 ( 32)	48 ( 22)	11 ( 5)	5 ( 2)	22 ( 8)	17 ( 6)	3 ( 1)	0 ( 0)
Pruritus	9 ( 4)	4 ( 2)	3 ( 1)	0 ( 0)	21 ( 7)	25 ( 9)	< 1%	0 ( 0)
Nervous system disorders
Paresthesia e	< 1%	0 ( 0)	0 ( 0)	0 ( 0)	39 ( 13)	30 ( 11)	< 1%	0 ( 0)
Peripheral neuropathy* e	34 ( 15)	30 ( 14)	8 ( 4)	8 ( 4)	29 ( 10)	15 ( 5)	4 ( 1)	< 1%
Headache d	11 ( 5)	8 ( 4)	5 ( 2)	< 1%	25 ( 9)	21 ( 8)	0 ( 0)	0 ( 0)
Investigations
Alanine aminotransferase increased	16 ( 7)	3 ( 1)	8 ( 4)	0 ( 0)	5 ( 2)	5 ( 2)	0 ( 0)	< 1%
Aspartate aminotransferase increased d	13 ( 6)	5 ( 2)	6 ( 3)	0 ( 0)	< 1%	5 ( 2)	0 ( 0)	0 ( 0)
Metabolism and nutrition disorders
Hypokalemia	24 ( 11)	13 ( 6)	16 ( 7)	12 ( 5)	12 ( 4)	< 1%	< 1%	0 ( 0)
Dehydration	9 ( 4 )	5 ( 2)	7 ( 3)	3 ( 1)	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)
Hypophosphatemia d	16 ( 7)	15 ( 7)	13 ( 6)	14 ( 6)	0 ( 0)	< 1%	0 ( 0)	0 ( 0)
Musculoskeletal and connective tissue disorders
Muscle spasms e	0 ( 0)	< 1%	0 ( 0)	0 ( 0)	98 ( 33)	43 ( 15)	< 1%	0 ( 0)
Myalgia e	7 ( 3)	8 ( 4)	3 ( 1)	5 ( 2)	19 ( 6)	12 ( 4)	< 1%	< 1%
Musculoskeletal pain e	< 1%	< 1%	0 ( 0)	0 ( 0)	19 ( 6)	11 ( 44)	0 ( 0)	0 ( 0)
Hepatobiliary disorders
Hyperbilirubinemia e	34 ( 15)	19 ( 9)	4 ( 2)	< 1%	4 ( 1)	< 1%	< 1%	0 ( 0)
Respiratory, thoracic and mediastinal disorders
Cough e	23 ( 10)	12 ( 5)	3 ( 1)	< 1%	80 ( 27)	56 ( 20)	0 ( 0)	0 ( 0)
Dyspnea c e	15 ( 7)	9 ( 4)	8 ( 4)	4 ( 2)	17 ( 6)	9 ( 3)	< 1%	0 ( 0)
Rhinorrhea e	0 ( 0)	3 ( 1)	0 ( 0)	0 ( 0)	15 ( 5)	6 ( 2)	0 ( 0)	0 ( 0)
Pulmonary embolism c d e	0 ( 0)	0 ( 0)	0 ( 0)	0 ( 0)	3 ( 1)	0 ( 0)	< 1%	0 ( 0)
Vascular disorders
Deep vein thrombosis*c d %	8 ( 4)	< 1%	5 ( 2)	< 1%	7 ( 2)	< 1%	4 ( 1)	< 1%
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Myelodysplastic syndrome c d e	5 ( 2)	0 ( 0)	< 1%	0 ( 0)	3 ( 1)	0 ( 0)	< 1%	0 ( 0)

After At Least One Prior Therapy for MM:

Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Table 6: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

Body System Adverse Reaction	REVLIMID/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	149 (42)	22 ( 6)
Anemia@	111 (31)	83 (24)
Thrombocytopenia@	76 (22)	37 (11)
Leukopenia	28 ( 8)	4 ( 1)
Lymphopenia	19 ( 5)	5 ( 1)
General disorders and administration site conditions
Fatigue	155 (44)	146 (42)
Pyrexia	97 (27)	82 (23)
Peripheral edema	93 (26)	74 (21)
Chest pain	29 ( 8)	20 ( 6)
Lethargy	24 ( 7)	8 ( 2)
Gastrointestinal disorders
Constipation	143 (41)	74 (21)
Diarrhea@	136 (39)	96 (27)
Nausea@	92 (26)	75 (21)
Vomiting@	43 (12)	33 ( 9)
Abdominal pain@	35 ( 10)	22 ( 6)
Dry mouth	25 ( 7)	13 ( 4)
Musculoskeletal and connective tissue disorders
Muscle cramp	118 (33)	74 (21)
Back pain	91 (26)	65 (19)
Bone pain	48 (14)	39 (11)
Pain in limb	42 (12)	32 ( 9)
Nervous system disorders
Dizziness	82 (23)	59 (17)
Tremor	75 (21)	26 ( 7)
Dysgeusia	54 (15)	34 ( 10)
Hypoesthesia	36 (10)	25 ( 7)
Neuropathya	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)
Infectionsb 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
Rashc	75 (21)	33 ( 9)
Sweating increased	35 ( 10)	25 ( 7)
Dry skin	33 ( 9)	14 ( 4)
Pruritus	27 ( 8)	18 ( 5)
Metabolism and nutrition disorders
Anorexia	55 (16)	34 ( 10)
Hypokalemia	48 (14)	21 ( 6)
Hypocalcemia	31 ( 9)	10 ( 3)
Appetite decreased	24 ( 7)	14 ( 4)
Dehydration	23 ( 7)	15 ( 4)
Hypomagnesemia	24 ( 7)	10 ( 3)
Investigations
Weight decreased	69 (20)	52 (15)
Eye disorders
Blurred vision	61 (17)	40 (11)
Vascular disorders
Deep vein thrombosis%	33 ( 9)	15 ( 4)
Hypertension	28 ( 8)	20 ( 6)
Hypotension	25 ( 7)	15 ( 4)

Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone groups

Body System Adverse Reaction	REVLIMID/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	118 (33)	12 ( 3)
Thrombocytopenia@	43 (12)	22 ( 6)
Anemia@	35 ( 10)	20 ( 6)
Leukopenia	14 ( 4)	< 1%
Lymphopenia	10 ( 3)	4 ( 1)
Febrile neutropenia%	8 ( 2)	0 ( 0)
General disorders and administration site conditions
Fatigue	23 ( 7)	17 ( 5)
Vascular disorders
Deep vein thrombosis%	29 ( 8)	12 ( 3)
Infections and infestations
Pneumonia@	30 ( 8)	19 ( 5)
Urinary tract infection	5 ( 1)	< 1%
Metabolism and nutrition disorders
Hypokalemia	17 ( 5)	5 ( 1)
Hypocalcemia	13 ( 4)	6 ( 2)
Hypophosphatemia	9 ( 3)	0 ( 0)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism@	14 ( 4)	< 1%
Respiratory distress@	4 ( 1)	0 ( 0)
Musculoskeletal and connective tissue disorders
Muscle weakness	20 ( 6)	10 ( 3)
Gastrointestinal disorders
Diarrhea@	11 ( 3)	4 ( 1)
Constipation	7 ( 2)	< 1%
Nausea@	6 ( 2)	< 1%
Cardiac disorders
Atrial fibrillation@	13 ( 4)	4 ( 1)
Tachycardia	6 ( 2)	< 1%
Cardiac failure congestive@	5 ( 1)	< 1%
Nervous system disorders
Syncope	10 ( 3)	< 1%
Dizziness	7 ( 2)	< 1%
Eye disorders
Cataract	6 ( 2)	< 1%
Cataract unilateral	5 ( 1)	0 ( 0)
Psychiatric disorder
Depression	10 ( 3)	6 ( 2)

Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

Body System Adverse Reaction	REVLIMID/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
For Tables 6, 7 and 8 above: @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).
Blood and lymphatic system disorders
Febrile neutropenia%	6 ( 2)	0 ( 0)
Vascular disorders
Deep vein thrombosis%	26 ( 7)	11 ( 3)
Infections and infestations
Pneumonia@	33 ( 9)	21 ( 6)
Respiratory, thoracic, and mediastinal disorders
Pulmonary embolism@	13 ( 4)	< 1%
Cardiac disorders
Atrial fibrillation@	11 ( 3)	< 1%
Cardiac failure congestive@	5 ( 1)	0 ( 0)
Nervous system disorders
Cerebrovascular accident@	7 ( 2)	< 1%
Gastrointestinal disorders
Diarrhea @	6 ( 2)	< 1%
Musculoskeletal and connective tissue disorders
Bone pain	4 ( 1)	0 ( 0)

Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.4)]

VTE and ATE are increased in patients treated with REVLIMID.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia

Cardiac disorders: bradycardia, myocardial infarction, angina pectoris

Endocrine disorders: hirsutism

Eye disorders: blindness, ocular hypertension

Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia

General disorders and administration site conditions: malaise

Investigations: liver function tests abnormal, alanine aminotransferase increased

Nervous system disorders: cerebral ischemia

Psychiatric disorders: mood swings, hallucination, loss of libido

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: cough, hoarseness

Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation

Myelodysplastic Syndromes:

A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient's underlying disease.

Table 9: Summary of Adverse Reactions Reported in ≥5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study

a Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are 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.
Body System Adverse Reaction a	10 mg Overall (N=148)
Patients with at least one adverse reaction	148 (100)
Blood and Lymphatic System Disorders
Thrombocytopenia	91 (61)
Neutropenia	87 (59)
Anemia	17 (11)
Leukopenia	12 (8)
Febrile Neutropenia	8 (5)
Skin and Subcutaneous Tissue Disorders
Pruritus	62 (42)
Rash	53 (36)
Dry Skin	21 (14)
Contusion	12 (8)
Night Sweats	12 (8)
Sweating Increased	10 (7)
Ecchymosis	8 (5)
Erythema	8 (5)
Gastrointestinal Disorders
Diarrhea	72 (49)
Constipation	35 (24)
Nausea	35 (24)
Abdominal Pain	18 (12)
Vomiting	15 (10)
Abdominal Pain Upper	12 (8)
Dry Mouth	10 (7)
Loose Stools	9 (6)
Respiratory, Thoracic and Mediastinal Disorders
Nasopharyngitis	34 (23)
Cough	29 (20)
Dyspnea	25 (17)
Pharyngitis	23 (16)
Epistaxis	22 (15)
Dyspnea Exertional	10 (7)
Rhinitis	10 (7)
Bronchitis	9 (6)
General Disorders and Administration Site Conditions
Fatigue	46 (31)
Pyrexia	31 (21)
Edema Peripheral	30 (20)
Asthenia	22 (15)
Edema	15 (10)
Pain	10 (7)
Rigors	9 (6)
Chest Pain	8 (5)
Musculoskeletal and Connective Tissue Disorders
Arthralgia	32 (22)
Back Pain	31 (21)
Muscle Cramp	27 (18)
Pain in Limb	16 (11)
Myalgia	13 (9)
Peripheral Swelling	12 (8)
Nervous System Disorders
Dizziness	29 (20)
Headache	29 (20)
Hypoesthesia	10 (7)
Dysgeusia	9 (6)
Peripheral Neuropathy	8 (5)
Infections and Infestations
Upper Respiratory Tract Infection	22 (15)
Pneumonia	17 (11)
Urinary Tract Infection	16 (11)
Sinusitis	12 (8)
Cellulitis	8 (5)
Metabolism and Nutrition Disorders
Hypokalemia	16 (11)
Anorexia	15 (10)
Hypomagnesemia	9 (6)
Investigations
Alanine Aminotransferase Increased	12 (8)
Psychiatric Disorders
Insomnia	15 (10)
Depression	8 (5)
Renal and Urinary Disorders
Dysuria	10 (7)
Vascular Disorders
Hypertension	9 (6)
Endocrine Disorders
Acquired Hypothyroidism	10 (7)
Cardiac Disorders
Palpitations	8 (5)

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions ¹ Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

1 Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. 2 Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.
Adverse Reactions 2	10 mg (N=148)
Patients with at least one Grade 3/4 AE	131 (89)
Neutropenia	79 (53)
Thrombocytopenia	74 (50)
Pneumonia	11 (7)
Rash	10 (7)
Anemia	9 (6)
Leukopenia	8 (5)
Fatigue	7 (5)
Dyspnea	7 (5)
Back Pain	7 (5)
Febrile Neutropenia	6 (4)
Nausea	6 (4)
Diarrhea	5 (3)
Pyrexia	5 (3)
Sepsis	4 (3)
Dizziness	4 (3)
Granulocytopenia	3 (2)
Chest Pain	3 (2)
Pulmonary Embolism	3 (2)
Respiratory Distress	3 (2)
Pruritus	3 (2)
Pancytopenia	3 (2)
Muscle Cramp	3 (2)
Respiratory Tract Infection	2 (1)
Upper Respiratory Tract Infection	2 (1)
Asthenia	2 (1)
Multi-organ Failure	2 (1)
Epistaxis	2 (1)
Hypoxia	2 (1)
Pleural Effusion	2 (1)
Pneumonitis	2 (1)
Pulmonary Hypertension	2 (1)
Vomiting	2 (1)
Sweating Increased	2 (1)
Arthralgia	2 (1)
Pain in Limb	2 (1)
Headache	2 (1)
Syncope	2 (1)

In other clinical studies of REVLIMID in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported:

Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction

Ear and labyrinth disorders: vertigo

Endocrine disorders: Basedow's disease

Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure

Immune system disorders: hypersensitivity

Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis

Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased

Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia

Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic

Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack

Psychiatric disorders: confusional state

Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass

Reproductive system and breast disorders: pelvic pain

Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing

Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis

Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis

Mantle Cell Lymphoma:

In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions.

Table 11: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma

1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects. 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects. $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects. @ - Adverse reactions where at least one resulted in a fatal outcome. % - Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases). # - All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered uled. + - All adverse reactions under HLT of Rash will be considered uled.
Body System Adverse Reaction	All Adverse Reactions1 (N=134)n (%)	Grade 3/4 Adverse Reactions2 (N=134) n (%)
General disorders and administration site conditions
Fatigue	45 (34)	9 (7)
Pyrexia$	31 (23)	3 (2)
Edema peripheral	21 (16)	0
Asthenia$	19 (14)	4 (3)
General physical health deterioration	3 (2)	2 (1)
Gastrointestinal disorders
Diarrhea$	42 (31)	8 (6)
Nausea$	40 (30)	1 (<1)
Constipation	21 (16)	1 (<1)
Vomiting$	16 (12)	1 (<1)
Abdominal pain$	13 (10)	5 ( 4)
Musculoskeletal and connective tissue disorders
Back pain	18 (13)	2 (1)
Muscle spasms	17 (13)	1 (<1)
Arthralgia	11 (8)	2 (1)
Muscular weakness$	8 (6)	2 ( 1)
Respiratory, thoracic and mediastinal disorders
Cough	38 (28)	1 (<1)
Dyspnea$	24 (18)	8 (6)
Pleural Effusion	10 (7)	2 (1)
Hypoxia	3 (2)	2 (1)
Pulmonary embolism	3 (2)	2 ( 1)
Respiratory distress$	2 (1)	2 (1)
Oropharyngeal pain	13 (10)	0
Infections and infestations
Pneumonia@ $	19 (14)	12 (9)
Upper respiratory tract infection	17 (13)	0
Cellulitis$	3 (2)	2 (1)
Bacteremia$	2 (1)	2 (1)
Staphylococcal sepsis$	2 (1)	2 (1)
Urinary tract infection$	5 (4)	2 (1)
Skin and subcutaneous tissue disorders
Rash +	30 (22)	2 (1)
Pruritus	23 (17)	1 (<1)
Blood and lymphatic system disorders
Neutropenia	65 (49)	58 (43)
Thrombocytopenia% $	48 (36)	37 (28)
Anemia$	41 (31)	15 (11)
Leukopenia$	20 (15)	9 (7)
Lymphopenia	10 ( 7)	5 (4)
Febrile neutropenia$	8 (6)	8 (6)
Metabolism and nutrition disorders
Decreased appetite	19 (14)	1 (<1)
Hypokalemia	17 (13)	3 (2)
Dehydration$	10 (7)	4 (3)
Hypocalcemia	4 (3)	2 (1)
Hyponatremia	3 (2)	3 (2)
Renal and urinary disorders
Renal failure$	5 (4)	2 (1)
Vascular disorders
Hypotension@ $	9 (7)	4 (3)
Deep vein thrombosis$	5 (4)	5 (4)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Tumor flare	13 (10)	0
Squamous cell carcinoma of skin$	4 (3)	4 (3)
Investigations
Weight decreased	17 (13)	0

The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Cardiac disorder: Cardiac failure

Ear and labyrinth disorders: Vertigo

General disorders and administration site conditions: Chills

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes

Musculoskeletal and connective tissue disorders: Pain in extremity

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy

Psychiatric disorders: Insomnia

Skin and subcutaneous tissue disorders: Dry skin, night sweats

The following serious adverse reactions not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Blood and lymphatic system disorders: Neutropenia

Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia

Infections and infestations: Clostridium difficile colitis, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma

Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism

Follicular Lymphoma or Marginal Zone Lymphoma

The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N=176) and MAGNIFY (N=222) [see Clinical Studies (14.4)]. Subjects were 18 years or older in age, had an ECOG PS ≤2, ANC ≥1,000 cells/mm³ and platelets≥ 75,000/mm³ (unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥8g/dL, AST and ALT ≤ 3 x ULN (unless documented liver involvement with lymphoma, and creatinine clearance of ≥ 30mL/min. Subjects with active HIV, hepatitis B or C were not eligible.

In the AUGMENT trial, patients received REVLIMID 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m² 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/m² weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=180) for up to 12 cycles. In the MAGNIFY trial, patients received REVLIMID 20 mg by mouth daily, days 1-21 of each 28 day cycle with rituximab 375 mg/m² weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 5, 7, 9 and 11 in the induction phase of the trial (n=222). In the AUGMENT trial, 88.1% of patients completed at least 6 cycles of REVLIMID/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6 cycles of REVLIMID/rituximab, and 30.6% of patients completed 12 cycles.

Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White.

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving REVLIMID/rituximab in AUGMENT and 29% in MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was neutropenia (4.8%).

The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%).

Table 12: All Grade Adverse Reactions ( ≥5%) or Grade 3/4 Adverse Reactions ( ≥1%) in Patients with FL and MZL with a Difference Between Arms of >1% When Compared to Control Arm in AUGMENT Trial

Note : Adverse reactions are coded to body system/adverse reaction using MedDRA 21. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse reaction. 1 All treatment-emergent AEs in at least 5% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 2 All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 3 All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). $ Serious ADR reported. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).*Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]):a "Thromboembolic events" combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis.b "Cough" combined AE term includes the following PTs: cough and productive cough.
c “Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper.d "Rash" combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and rash generalized.e "Pruritus" combined AE term includes the following PTs: pruritus, pruritus generalized, rash pruritic, and pruritus allergic.
	All Adverse Reactions 1		Grade 3 / 4 Adverse Reactions 2
Body System Adverse Reaction*	REVLIMID + Rituximab Arm (N=176) n (%)	Rituximab + Placebo (Control Arm) (N=180) n (%)	REVLIMID + Rituximab Arm (N=176) n (%)	Rituximab + Placebo (Control Arm) (N=180) n (%)
Infections and infestations
Upper respiratory tract infection	32 (18)	23 (13)	2 (1.1)	4 (2.2)
Influenza %	17 (10)	8 (4.4)	1 (< 1)	0 (0)
Pneumonia 3,$,%	13 (7)	6 (3.3)	6 (3.4)	4 (2.2)
Sinusitis	13 (7)	5 (2.8)	0 (0)	0 (0)
Urinary tract infection$	13 (7)	7 (3.9)	1 (< 1)	1 (< 1)
Bronchitis	8 (4.5)	6 (3.3)	2 (1.1)	0 (0)
Gastroenteritis $	6 (3.4)	4 (2.2)	2 (1.1)	0 (0)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Tumor flare $	19 (11)	1 (< 1)	1 (< 1)	0 (0)
Blood and lymphatic disorders
Neutropenia 3,$, %	102 (58)	40 (22)	88 (50)	23 (13)
Leukopenia $,%	36 (20)	17 (9)	12 (7)	3 (1.7)
Anemia 3,$	28 (16)	8 (4.4)	8 (4.5)	1 (< 1)
Thrombocytopenia 3,$,%	26 (15)	8 (4.4)	4 (2.3)	2 (1.1)
Lymphopenia	8 (4.5)	14 (8)	5 (2.8)	2 (1.1)
Febrile Neutropenia 3,$,%	5 (2.8)	1 (< 1)	5 (2.8)	1 (< 1)
Metabolism and nutrition disorders
Decreased Appetite	23 (13)	11 (6)	2 (1.1)	0 (0)
Hypokalemia %	14 (8)	5 (2.8)	4 (2.3)	0 (0)
Hyperuricemia	10 (6)	8 (4.4)	1 (< 1)	1 (< 1)
Nervous system disorders
Headache	26 (15)	17 (9)	1 (< 1)	0 (0)
Dizziness	15 (9)	9 (5)	0 (0)	0 (0)
Vascular disorders
Hypotension %	9 (5)	1 (< 1)	1 (< 1)	0 (0)
Thromboembolic events a,$	8 (4.5)	2 (1.1)	4 (2.3)	2 (1.1)
Respiratory, thoracic and mediastinal disorders
Cough b	43 (24)	35 (19)	1 (< 1)	0 (0)
Dyspnea $	19 (11)	8 (4.4)	2 (1.1)	1 (< 1)
Oropharyngeal pain	10 (6)	8 (4.4)	0 (0)	0 (0)
Pulmonary Embolism 3,$	4 (2.3)	1 (< 1)	4 (2.3)	1 (< 1)
Chronic obstructive pulmonary disease $	3 (1.7)	0 (0)	2 (1.1)	0 (0)
Respiratory failure 3,$	2 (1.1)	1 (< 1)	2 (1.1)	0 (0)
Gastrointestinal disorders
Diarrhea $,%	55 (31)	41 (23)	5 (2.8)	0 (0)
Constipation	46 (26)	25 (14)	0 (0)	0 (0)
Abdominal pain c ,$	32 (18)	20 (11)	2 (1.1)	0 (0)
Vomiting $	17 (10)	13 (7)	0 (0)	0 (0)
Dyspepsia	16 (9)	5 (2.8)	0 (0)	0 (0)
Stomatitis	9 (5)	7 (3.9)	0 (0)	0 (0)
Skin and subcutaneous tissue disorders
Rash $,d	39 (22)	14 (8)	5 (2.8)	2 (1.1)
Pruritus $,e	36 (20)	9 (5)	2 (1.1)	0 (0)
Dry skin	9 (5)	6 (3.3)	0 (0)	0 (0)
Dermatitis acneiform	8 (4.5)	0 (0)	2 (1.1)	0 (0)
Musculoskeletal and connective tissue disorders
Muscle Spasms	23 (13)	9 (5)	1 (< 1)	1 (< 1)
Pain in Extremity $	8 (4.5)	9 (5)	2 (1)	0 (0)
Renal disorders
Acute Kidney Injury 3,$,@,%	3 (1.7)	0 (0)	2 (1.1)	0 (0)
Cardiac disorders
Supraventricular tachycardia 3,$	2 (1.1)	0 (0)	2 (1.1)	0 (0)
General disorders and administration site conditions
Fatigue	38 (22)	33 (18)	2 (1.1)	1 (< 1)
Pyrexia 3,$	37 (21)	27 (15)	1 (< 1)	3 (1.7)
Asthenia $,%	24 (14)	19 (11)	2 (1.1)	1 (< 1)
Edema Peripheral $	23 (13)	16 (9)	0 (0)	0 (0)
Chills	14 (8)	8 (4.4)	0 (0)	0 (0)
Malaise	13 (7)	10 (6)	0 (0)	0 (0)
Influenza like illness	9 (5)	7 (3.9)	0 (0)	0 (0)
Psychiatric disorders
Insomnia	14 (8)	11 (6)	0 (0)	0 (0)
Investigations
Alanine Aminotransferase Increased	18 (10)	15 (8)	3 (1.7)	1 (< 1)
WBC count decreased	16 (9)	13 (7)	5 (2.8)	2 (1.1)
Lymphocyte count decreased	12 (7)	12 (7)	6 (3.4)	2 (1.1)
Blood bilirubin increased	10 (6)	0 (0)	0 (0)	0 (0)
Weight Decreased	12 (7)	2 (1.1)	0 (0)	0 (0)

6.2 Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.8 to 5.11, and 5.13)]

Endocrine disorders: Hypothyroidism, hyperthyroidism

Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests

Immune system disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection

Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)

Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)