6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in detail in other labeling sections:

•: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1, 5.2)]
•: Venous and Arterial Thromboembolism [see Warnings and Precautions (5.3)]
•: Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.4)]
•: Hematologic Toxicity [see Warnings and Precautions (5.5)]
•: Hepatotoxicity [see Warnings and Precautions (5.6)]
•: Severe Cutaneous Reactions [see Warnings and Precautions (5.7)]
•: Dizziness and Confusional State [see Warnings and Precautions (5.8)]
•: Neuropathy [see Warnings and Precautions (5.9)]
•: Risk of Second Primary Malignancies [see Warnings and Precautions (5.10)]
•: Tumor Lysis Syndrome [see Warnings and Precautions (5.11)]
•: Hypersensitivity [see Warnings and Precautions (5.12)]

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.

Multiple Myeloma (MM)

In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%.

In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with POMALYST + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5. In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks. Eight percent of patients discontinued POMALYST due to adverse reactions.

Tables 3 and 4 summarize the adverse reactions reported in Trials 1 and 2, respectively.

Table 3: Adverse Reactions in Any POMALYST Treatment Arm in Trial 1*
* Regardless of attribution of relatedness to POMALYST. a POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any POMALYST treatment arm. Data cutoff: 01 March 2013
	All Adverse Reactions ≥10% in Either Arm		Grade 3 or 4 ≥5% in Either Arm
Body System Adverse Reaction	POMALYSTa (N=107)	POMALYST + Low-dose Dex (N=112)	POMALYST (N=107)	POMALYST + Low-dose Dex (N=112)
Number (%) of patients with at least one adverse reaction	107 (100)	112 (100)	98 (92)	102 (91)
Blood and lymphatic system disorders
Neutropenia b	57 (53)	55 (49)	51 (48)	46 (41)
Anemia b	41 (38)	47 (42)	25 (23)	24 (21)
Thrombocytopenia b	28 (26)	26 (23)	24 (22)	21 (19)
Leukopenia	14 (13)	22 (20)	7 (7)	11 (10)
Febrile neutropenia b	<10%	<10%	6 (6)	3 (3)
Lymphopenia	4 (4)	17 (15)	2 (2)	8 (7)
General disorders and administration site conditions
Fatigue and asthenia b	62 (58)	70 (63)	13 (12)	19 (17)
Edema peripheral	27 (25)	19 (17)	0 (0.0)	0 (0.0)
Pyrexia b	25 (23)	36 (32)	<5%	<5%
Chills	11 (10)	14 (13)	0 (0.0)	0 (0.0)
Gastrointestinal disorders
Nausea b	39 (36)	27 (24)	<5%	<5%
Constipation b	38 (36)	41 (37)	<5%	<5%
Diarrhea	37 (35)	40 (36)	<5%	<5%
Vomiting b	15 (14)	16 (14)	<5%	0 (0.0)
Musculoskeletal and connective tissue disorders
Back pain b	37 (35)	36 (32)	15 (14)	11 (10)
Musculoskeletal chest pain	25 (23)	22 (20)	<5%	0 (0.0)
Muscle spasms	23 (21)	22 (20)	<5%	<5%
Arthralgia	18 (17)	17 (15)	<5%	<5%
Muscular weakness	15 (14)	15 (13)	6 (6)	4 (4)
Bone pain	13 (12)	8 (7)	<5%	<5%
Musculoskeletal pain	13 (12)	19 (17)	<5%	<5%
Pain in extremity	8 (7)	16 (14)	0 (0.0)	<5%
Infections and infestations
Upper respiratory tract infection	40 (37)	32 (29)	<5%	<5%
Pneumonia b	30 (28)	38 (34)	21 (20)	32 (29)
Urinary tract infection b	11 (10)	19 (17)	2 (2)	10 (9)
Sepsis b	<10%	<10%	6 (6)	5 (4)
Metabolism and nutrition disorders
Decreased appetite	25 (23)	21 (19)	<5%	0 (0.0)
Hypercalcemia b	23 (21)	13 (12)	11 (10)	1 (<1)
Hypokalemia	13 (12)	13 (12)	<5%	<5%
Hyperglycemia	12 (11)	17 (15)	<5%	<5%
Hyponatremia	12 (11)	14 (13)	<5%	<5%
Dehydration b	<10%	<10%	5 (4.7)	6 (5.4)
Hypocalcemia	6 (6)	13 (12)	0 (0.0)	<5%
Respiratory, thoracic and mediastinal disorders
Dyspnea b	38 (36)	50 (45)	8 (7)	14 (13)
Cough	18 (17)	25 (22)	0 (0.0)	0 (0.0)
Epistaxis	18 (17)	12 (11)	<5%	0 (0.0)
Productive cough	10 (9)	14 (13)	0 (0.0)	0 (0.0)
Oropharyngeal pain	6 (6)	12 (11)	0 (0.0)	0 (0.0)
Nervous system disorders
Dizziness	24 (22)	20 (18)	<5%	<5%
Peripheral neuropathy	23 (21)	20 (18)	0 (0.0)	0 (0.0)
Headache	16 (15)	15 (13)	0 (0.0)	<5%
Tremor	11 (10)	15 (13)	0 (0.0)	0 (0.0)
Skin and subcutaneous tissue disorders
Rash	22 (21)	18 (16)	0 (0.0)	<5%
Pruritus	16 (15)	10 (9)	0 (0.0)	0 (0.0)
Dry skin	10 (9)	12 (11)	0 (0.0)	0 (0.0)
Hyperhidrosis	8 (7)	18 (16)	0 (0.0)	0 (0.0)
Night sweats	5 (5)	14 (13)	0 (0.0)	0 (0.0)
Investigations
Blood creatinine increased b	20 (19)	11 (10)	6 (6)	3 (3)
Weight decreased	16 (15)	10 (9)	0 (0.0)	0 (0.0)
Weight increased	1 (<1)	12 (11)	0 (0.0)	0 (0.0)
Psychiatric disorders
Anxiety	14 (13)	8 (7)	0 (0.0)	0 (0.0)
Confusional state b	13 (12)	15 (13)	6 (6)	3 (3)
Insomnia	7 (7)	18 (16)	0 (0.0)	0 (0.0)
Renal and urinary disorders
Renal failure b	16 (15)	11 (10)	9 (8)	8 (7)

Table 4: Adverse Reactions in Trial 2
a Percentage did not meet the criteria to be considered as an adverse reaction for POMALYST for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013
	All Adverse Reactions (≥5% in POMALYST + Low-dose Dex arm, and at least 2% higher than the High-dose-Dex arm)		Grade 3 or 4 (≥1% in POMALYST + Low-dose Dex arm, and at least 1% higher than the High-dose-Dex arm)
Body System Adverse Reaction	POMALYST + Low-dose Dex (N=300)	High-dose Dex (N=150)	POMALYST + Low-dose Dex (N=300)	High-dose Dex (N=150)
Number (%) of patients with at least one adverse reaction	297 (99)	149 (99)	259 (86)	127 (85)
Blood and lymphatic system disorders
Neutropenia b	154 (51)	31 (21)	145 (48)	24 (16)
Thrombocytopenia	89 (30) a	44 (29) a	66 (22) a	39 (26) a
Leukopenia	38 (13)	8 (5)	27 (9)	5 (3)
Febrile neutropenia b	28 (9)	0 (0.0)	28 (9)	0 (0.0)
General disorders and administration site conditions
Fatigue and asthenia	140 (47)	64 (43)	26 (9) a	18 (12) a
Pyrexia b	80 (27)	35 (23)	9 (3) a	7 (5) a
Edema peripheral	52 (17)	17 (11)	4 (1) a	3 (2) a
Pain	11 (4) a	3 (2) a	5 (2)	1 (<1)
Infections and infestations
Upper respiratory tract infection b	93 (31)	19 (13)	9 (3)	1 (<1)
Pneumonia b	58 (19)	20 (13)	47 (16)	15 (10)
Neutropenic sepsis b	3 (1) a	0 (0.0) a	3 (1)	0 (0.0)
Gastrointestinal disorders
Diarrhea	66 (22)	28 (19)	3 (1) a	2 (1) a
Constipation	65 (22)	22 (15)	7 (2)	0 (0.0)
Nausea	45 (15)	17 (11)	3 (1) a	2 (1) a
Vomiting	23 (8)	6 (4)	3 (1)	0 (0.0)
Musculoskeletal and connective tissue disorders
Back pain b	59 (20)	24 (16)	15 (5)	6 (4)
Bone pain b	54 (18)	21 (14)	22 (7)	7 (5)
Muscle spasms	46 (15)	11 (7)	1 (<1) a	1 (<1) a
Arthralgia	26 (9)	7 (5)	2 (<1) a	1 (<1) a
Pain in extremity	20 (7) a	9 (6) a	6 (2)	0 (0.0)
Respiratory, thoracic and mediastinal disorders
Dyspnea b	76 (25)	25 (17)	17 (6)	7 (5)
Cough	60 (20)	15 (10)	2 (<1) a	1 (<1) a
Chronic obstructive pulmonary disease b	5 (2) a	0 (0.0) a	4 (1)	0 (0.0)
Nervous system disorders
Peripheral neuropathy	52 (17)	18 (12)	5 (2) a	2 (1) a
Dizziness	37 (12)	14 (9)	4 (1) a	2 (1) a
Headache	23 (8)	8 (5)	1 (<1) a	0 (0.0) a
Tremor	17 (6)	2 (1)	2 (<1) a	0 (0.0) a
Depressed level of consciousness	5 (2) a	0 (0.0) a	3 (1)	0 (0.0)
Metabolism and nutrition disorders
Decreased appetite	38 (13)	12 (8)	3 (1) a	2 (1) a
Hypokalemia	28 (9) a	12 (8) a	12 (4)	4 (3)
Hypocalcemia	12 (4) a	9 (6) a	5 (2)	1 (<1)
Skin and subcutaneous tissue disorders
Rash	23 (8)	2 (1)	3 (1)	0 (0.0)
Pruritus	22 (7)	5 (3)	0 (0.0) a	0 (0.0) a
Hyperhidrosis	15 (5)	1 (<1)	0 (0.0) a	0 (0.0) a
Investigations
Neutrophil count decreased	15 (5)	1 (<1)	14 (5)	1 (<1)
Platelet count decreased	10 (3) a	3 (2) a	8 (3)	2 (1)
White blood cell count decreased	8 (3) a	1 (<1) a	8 (3)	0 (0.0)
Alanine aminotransferase increased	7 (2) a	2 (1) a	5 (2)	0 (0.0)
Aspartate aminotransferase increased	4 (1) a	2 (1) a	3 (1)	0 (0.0)
Lymphocyte count decreased	3 (1) a	1 (<1) a	3 (1)	0 (0.0)
Renal and urinary disorders
Renal failure	31 (10) a	18 (12) a	19 (6)	8 (5)
Injury, poisoning and procedural complications
Femur fracture b	5 (2) a	1 (<1) a	5 (2)	1 (<1)
Reproductive system and breast disorders
Pelvic pain	6 (2) a	3 (2) a	4 (1)	0 (0.0)

Other Adverse Reactions

Other adverse reactions of POMALYST in patients with MM, not described above, and considered important:

Cardiac Disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive

Ear and Labyrinth Disorders: Vertigo

Gastrointestinal disorders: Abdominal pain

General Disorders and Administration Site Conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure

Hepatobiliary Disorders: Hyperbilirubinemia

Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection

Investigations: Alanine aminotransferase increased, Hemoglobin decreased

Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture

Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive

Nervous system disorders: Depressed level of consciousness, Syncope

Psychiatric disorders: Mental status change

Renal and urinary disorders: Urinary retention, Hyponatremia

Reproductive system and breast disorders: Pelvic pain

Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm

Vascular disorders: Hypotension

Kaposi Sarcoma (KS)

The safety of POMALYST in patients with KS was evaluated in Trial 12-C-0047 [see Clinical Studies (14.2)]. Twenty-eight patients received POMALYST 5 mg taken orally once daily on Days 1 through 21 of repeated 28-day cycles. The study excluded patients with procoagulant disorders or a history of venous or arterial thromboembolism. Patients received DVT prophylaxis with daily low dose aspirin. Across all patients treated on Trial 12-C-0047, 75% were exposed to pomalidomide for 6 months or longer and 25% were exposed for greater than one year.

Serious adverse reactions occurred in 18% (5/28) of patients who received POMALYST. The following serious adverse reactions each occurred in 1 patient: anemia, decreased neutrophil count, and hematuria.

Permanent discontinuation due to an adverse reaction occurred in 11% (3/28) of patients who received POMALYST.

Dosage interruptions due to an adverse reaction occurred in 14% (4/28) of patients who received POMALYST. The most frequent adverse reaction requiring dosage interruption was decreased neutrophil count, which occurred in 3 patients.

The POMALYST dose was reduced due to an adverse reaction in 1 patient due to gout.

Tables 5 and 6 summarize the adverse reactions and select laboratory abnormalities reported in Trial 12-C-0047.

Table 5: Adverse Reactions (≥ 20%) in Patients Who Received POMALYST in Trial 12-C-0047
Adverse Reaction	Grades 1-4 N=28 %	Grade 3 or 4 N=28 %
Rash, maculo-papular	71	3.6
Constipation	71	0
Fatigue	68	0
Nausea	36	0
Diarrhea	32	3.6
Cough	29	0
Dyspnea	29	0
Peripheral Edema	29	3.6
Upper respiratory tract infection	29	0
Muscle spasms	25	0
Hypothyroidism	21	0
Dry skin	21	0
Chills	21	0

Table 6: Frequency of Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients Who Received POMALYST in Trial 12-C-0047
* Denominator is the number of patients for whom there is a baseline and at least one post baseline assessment for the laboratory parameter.
Laboratory Abnormality	Grades 1-4* %	Grades 3-4* %
Hematology
Decreased Absolute Neutrophil Count	96	50
Decreased White Blood Cells	79	3.6
Decreased Hemoglobin	54	0
Decreased Platelets	54	0
Chemistry
Elevated Creatinine	86	3.6
Elevated Glucose	57	7
Decreased Albumin	54	0
Decreased Phosphate	54	25
Decreased Calcium	50	0
Increased Alanine Aminotransferase (ALT)	32	0
Increased Aspartate Aminotransferase (AST)	25	0
Elevated Creatine Kinase	25	7
Decreased Magnesium	14	0
Elevated Alkaline Phosphate	14	3.6

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of POMALYST. 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.

Blood and Lymphatic System Disorders: Pancytopenia

Endocrine Disorders: Hypothyroidism, hyperthyroidism

Gastrointestinal Disorders: Gastrointestinal hemorrhage

Hepatobiliary Disorders: Hepatic failure (including fatal cases), elevated liver enzymes

Immune system Disorders: Allergic reactions (e.g., angioedema, anaphylaxis, urticaria), solid organ transplant rejection

Infections and Infestations: Hepatitis B virus reactivation, Herpes zoster, progressive multifocal leukoencephalopathy (PML)

Neoplasms benign, malignant and unspecified (incl cysts and polyps): Tumor lysis syndrome, basal cell carcinoma, and squamous cell carcinoma of the skin

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)