Pomalyst Drug Information

• 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) ]
• MM: Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia ( 6.1 ).
• KS: Most common adverse reactions including laboratory abnormalities (≥30%) are decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea ( 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. 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 POMALYST a (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)

Drugs That Affect Pomalidomide Plasma Concentrations

CYP1A2 inhibitors : In healthy subjects, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased C max and AUC of pomalidomide by 24% and 125% respectively . Increased pomalidomide exposure may increase the risk of exposure related toxicities. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If co-administration is unavoidable, reduce the POMALYST dose .

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action and findings from animal studies, POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy . POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. Pomalidomide crossed the placenta after administration to pregnant rabbits (see Data ). If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day.

Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day.

Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day.

Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.

Following daily oral administration of pomalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma pomalidomide concentrations were approximately 50% of the maternal C max at all dosages (5 to 250 mg/kg/day), indicating that pomalidomide crossed the placenta.

Pediatric Use The safety and effectiveness of POMALYST have not been established in pediatric patients. The safety and effectiveness were assessed but not established in two open-label studies: a dose escalation study in 25 pediatric patients aged 5 to <17 with recurrent, progressive or refractory CNS tumors and a parallel-group study conducted in 47 pediatric patients aged 4 to <17 years with recurrent or progressive high-grade glioma, medulloblastoma, ependymoma, or diffuse intrinsic pontine glioma (DIPG). No new safety signals were observed in pediatric patients across these studies. At the same dose by body surface area, pomalidomide exposure in 55 pediatric patients aged 4 to < 17 years old was within the range observed in adult patients with MM but higher than the exposure observed in adult patients with KS .

• Pregnancy ( 4.1 )
• Hypersensitivity ( 4.2 ) 4.1 Pregnancy POMALYST is contraindicated in females who are pregnant. POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. 4.2 Hypersensitivity POMALYST is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients [see Warnings and Precautions (5.7) , Description (11) ] .

Hemodialysis can remove pomalidomide from circulation.