POMALYST- pomalidomide_capsule

Pomalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos and Ikaros) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma (MM) cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e. , TNF-alpha and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model. Pomalidomide exposure-response analyses showed that there was no relationship between systemic pomalidomide exposure level and efficacy or safety following pomalidomide dose of 4 mg. Cardiac Electrophysiology The QTc prolongation potential of pomalidomide was evaluated in a single center, randomized, double-blind crossover study (N=72) using 4 mg pomalidomide, 20 mg pomalidomide, placebo, and 400 mg moxifloxacin (positive control). No significant QTc prolongation effect of pomalidomide was observed following pomalidomide doses of 4 and 20 mg. In patients with MM who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC (CV%) of 860 (37%) ng∙h/mL and C max max Absorption Following administration of single oral doses of POMALYST, the maximum plasma concentration (C max Effect of Food Co-administration of POMALYST with a high-fat meal (approximately 50% of the total caloric content) and high-calorie meal (approximately 800 to 1000 calories) (the meal contained approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) delays the T max max Distribution Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state in patients with MM or KS. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~T max Human plasma protein binding of pomalidomide ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-gp. Elimination Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h in patients with MM or KS. Pomalidomide is eliminated with a median plasma half-life of 9. 5 hours in healthy subjects and 7. 5 hours in patients with MM or KS. Metabolism Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. Minor contributions from CYP2C19 and CYP2D6 were also observed in vitro Excretion Following a single oral administration of [ 14 Specific Populations Age (61 to 85 years old), sex and race have no clinically significant effect on the systemic exposure of pomalidomide. Patients with Renal Impairment Pomalidomide pharmacokinetic parameters were not significantly affected in patients with moderate (30 mL/min <= CLcr< 60 mL/min) or severe (15 mL/min <= CLcr< 30 mL/min) renal impairment relative to patients with normal renal function (CLcr >= 60 mL/min). Mean exposure (AUC) to pomalidomide increased by 38% in patients with severe renal impairment requiring dialysis (CLcr< 30 mL/min requiring dialysis) and 40% in patients with end stage renal disease (CLcr< 15 mL/min) on non-dialysis days. In patients with severe renal impairment requiring dialysis, the estimated dialysis clearance is approximately 12 L/h which is higher than pomalidomide total body clearance, indicating hemodialysis will remove pomalidomide from the blood circulation. Patients with Hepatic Impairment Mean exposure (AUC) of pomalidomide increased by 51%, 58% and 72% in subjects with mild, moderate or severe hepatic impairment as defined by Child-Pugh criteria, respectively. Drug Interaction Studies Clinical Studies Co-administration of POMALYST with the following drugs did not increase pomalidomide exposure to a clinically significant extent: ketoconazole (a strong CYP3A4 and P-gp inhibitor), carbamazepine (a strong CYP3A4 inducer) and dexamethasone (a weak to moderate CYP3A4 inducer). Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied. CYP1A2 Inhibitors: [see Dosage and Administration (2. 6) Drug Interactions (7. 1) Strong CYP3A4 and P-gp Inhibitors: Strong CYP1A2 Inducers: Strong CYP3A4 Inducers: Dexamethasone: Smoking: max In Vitro Studies Pomalidomide does not inhibit or induce cytochrome p450 enzymes or transporters in vitro.

POMALYST is a thalidomide analogue indicated for the treatment of adult patients: 1. 2 POMALYST, in combination with dexamethasone, is indicated for adult patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. POMALYST is indicated for the treatment of: This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.

7 Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 3) The recommended dosage of POMALYST is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give POMALYST in combination with dexamethasone [see Clinical Studies (14. 1) The recommended dosage of POMALYST is 5 mg once daily taken orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS) [see Clinical Studies (14. 2) Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of POMALYST in patients with multiple myeloma (MM) when the neutrophil count is at least 500 per mcL and the platelet count is at least 50,000 per mcL. Dosage modification for POMALYST for hematologic adverse reactions in patients with MM are summarized in Table 1. Table 1: Dosage Modifications for POMALYST for Hematologic in MM Adverse Reaction Severity Dosage Modification * Permanently discontinue POMALYST if unable to tolerate 1 mg once daily. Neutropenia [see Warnings and Precautions (5. 5) Thrombocytopenia [see Warnings and Precautions (5. 5) Kaposi Sarcoma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of POMALYST in patients with KS when the neutrophil count is at least 1000 per mcL and the platelet count is at least 75,000 per mcL. Dose modifications for POMALYST for hematologic adverse reactions in patients with KS are summarized in Table 2. Table 2: Dosage Modifications for POMALYST for Hematologic Adverse Reactions in KS Adverse Reaction Severity Dosage Modification * Permanently discontinue POMALYST if unable to tolerate 1mg once daily. 5) ANC 500 to less than 1,000 per mcL Day 1 of cycle During cycle ANC less than 500 per mcL Febrile Neutropenia [see Warnings and Precautions (5. 5) ANC less than 1,000 per mcL and single temperature greater than or equal to 38. 3°C Thrombocytopenia [see Warnings and Precautions (5. 5) Platelet count 25,000 to less than 50,000 per mcL Day 1 of cycle During cycle: Platelet count less than 25,000 per mcL Permanently discontinue POMALYST. Permanently discontinue POMALYST for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction [See Warnings and Precautions (5. 12) For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician's discretion. Avoid concomitant use of POMALYST with strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg [see Drug Interactions (7. 1) Clinical Pharmacology (12. 3) Take POMALYST after completion of dialysis procedure on hemodialysis days [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Multiple Myeloma For patients with MM with mild or moderate hepatic impairment (Child-Pugh A or B), reduce the recommended dosage to 3 mg orally daily. For patients with MM with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 2 mg [see Use in Specific Populations (8. 7) Clinical Pharmacology (12. 3) Kaposi Sarcoma For patients with KS with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C), reduce the recommended dosage to 3 mg orally daily [see Use in Specific Populations (8. 3) Swallow capsules whole with water. Do not break, chew, or open the capsules. POMALYST may be taken with or without food.

The following clinically significant adverse reactions are described in detail in other labeling sections: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5)] [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) [see Warnings and Precautions (5. 12) 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. gov/medwatch. 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. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4. 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 b All Adverse Reactions >=10% in Either Arm Grade 3 or 4 >=5% in Either Arm Body System 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) Pyrexia b 25 (23) 36 (32) <5% <5% Chills 11 (10) 14 (13) 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. 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) Epistaxis 18 (17) 12 (11) <5% 0 (0. 0) Productive cough 10 (9) 14 (13) 0 (0. 0) Oropharyngeal pain 6 (6) 12 (11) 0 (0. 0) Nervous system disorders Dizziness 24 (22) 20 (18) <5% <5% Peripheral neuropathy 23 (21) 20 (18) 0 (0. 0) Headache 16 (15) 15 (13) 0 (0. 0) <5% Tremor 11 (10) 15 (13) 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) Dry skin 10 (9) 12 (11) 0 (0. 0) Hyperhidrosis 8 (7) 18 (16) 0 (0. 0) Night sweats 5 (5) 14 (13) 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) Weight increased 1 (<1) 12 (11) 0 (0. 0) Psychiatric disorders Anxiety 14 (13) 8 (7) 0 (0. 0) Confusional state b 13 (12) 15 (13) 6 (6) 3 (3) Insomnia 7 (7) 18 (16) 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 b 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 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) 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 Hyperhidrosis 15 (5) 1 (<1) 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: Ear and Labyrinth Disorders: Gastrointestinal disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Infections and Infestations: Investigations: Injury, poisoning and procedural complications: Metabolism and nutritional disorders: Nervous system disorders: Psychiatric disorders: Renal and urinary disorders: Reproductive system and breast disorders: Respiratory, thoracic, and mediastinal disorders: Vascular disorders: Kaposi Sarcoma (KS) The safety of POMALYST in patients with KS was evaluated in Trial 12-C-0047 [see Clinical Studies (14. 2) 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 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: Endocrine Disorders: Gastrointestinal Disorders: Hepatobiliary Disorders: Immune system Disorders: Infections and Infestations: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Skin and Subcutaneous Tissue Disorders:.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM
WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects ( 4 5. 1 For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception ( 5. 3 POMALYST is available only through a restricted program called PS-Pomalidomide REMS ( 5. 2 Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Antithrombotic prophylaxis is recommended ( 5. 3 Embryo-Fetal Toxicity POMALYST is contraindicated in pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4) Warnings and Precautions (5. 1) Use in Specific Populations (8. 3) POMALYST is only available through a restricted distribution program called PS-Pomalidomide REMS [see Warnings and Precautions (5. 2) Venous and Arterial Thromboembolism Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient''s underlying risk factors [see Warnings and Precautions (5.
CONTRAINDICATIONS
2 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) Use in Specific Populations (8. 1) POMALYST is contraindicated in patients who have demonstrated severe hypersensitivity (e. , angioedema, anaphylaxis) to pomalidomide or any of the excipients [see Warnings and Precautions (5. 7) Description (11).

2 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 [see Clinical Pharmacology (12. 1) [see Contraindications (4) Warnings and Precautions (5. 1) 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 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U. 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 Risk Summary There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats (see Data Data Animal Data Following a single oral administration of pomalidomide to lactating rats approximately 14 days postpartum, pomalidomide was transferred into milk, with milk to plasma ratios of 0. Pregnancy Testing POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8. 1) Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Contraception Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception en dash tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner's vasectomy, and 1 additional effective contraceptive method en dash male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. Infertility Based on findings in animals, female fertility may be compromised by treatment with POMALYST [see Nonclinical Toxicology (13. 1) 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 [NCT02415153] 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) [NCT03257631]. 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 [see Clinical Pharmacology (12. 3) Multiple Myeloma Of the total number of patients in clinical studies of POMALYST, 44% were aged older than 65 years, while 10% were aged older than 75 years. No overall differences in effectiveness were observed between these patients and younger patients. In these studies, patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia. Kaposi Sarcoma Of the 28 patients who received POMALYST, 11% were 65 years or older, and 3. 6% were 75 years of age or older. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In patients with severe renal impairment requiring dialysis, the AUC of pomalidomide increased by 38% and the rate of SAE increased by 64% relative to patients with normal renal function; therefore, starting dose adjustment is recommended. For patients with severe renal impairment requiring dialysis, administer POMALYST after the completion of hemodialysis on dialysis days because exposure of pomalidomide could be significantly decreased during dialysis [see Dosage and Administration (2. 7) Clinical Pharmacology (12. 3) Pomalidomide is metabolized primarily by the liver. Following single dose administration, the AUC of pomalidomide increased 51%, 58%, and 72% in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively compared to subjects with normal liver function. Dose adjustment is recommended in patients with hepatic impairment [see Dosage and Administration (2. 8) Clinical Pharmacology (12. 3) Cigarette smoking reduces pomalidomide AUC due to CYP1A2 induction. Advise patients that smoking may reduce the efficacy of pomalidomide [see Clinical Pharmacology (12.

Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg ( 2. 3 CYP1A2 inhibitors In healthy subjects, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased C max [see Clinical Pharmacology (12. [see Dosage and Administration (2.

OVERDOSAGE
Hemodialysis can remove pomalidomide from circulation.
NONCLINICAL TOXICOLOGY
Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.
CLINICAL STUDIES
Trial 1 Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma (MM) who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive POMALYST alone or POMALYST with Low-dose Dex. In Trial 1, the safety and efficacy of POMALYST 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the POMALYST alone arm were allowed to add Low-dose Dex upon disease progression. Table 7 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms. Table 7: Baseline Demographic and Disease-Related Characteristics en dash Trial 1 POMALYST (n=108) POMALYST + Low-dose Dex (n=113) Data cutoff: 01 April 2011 Patient Characteristics Median age, years (range) 61 (37-88) 64 (34-88) Age distribution, n (%) <65 years 65 (60. 1) >=65 years 43 (39. 9) Sex, n (%) Male 57 (52. 9) Female 51 (47. 1) Race/ethnicity, n (%) White 86 (79. 4) Black or African American 16 (14. 8) 17 (15) All other race 6 (5. 6) ECOG Performance, n (%) Status 0-1 95 (87. 5) Disease Characteristics Number of prior therapies Median (min, max) 5 (2, 12) 5 (2, 13) Prior transplant, n (%) 82 (75. 3) Refractory to bortezomib and lenalidomide, n (%) 64 (59. 1) Table 8 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Trial 1. ORR did not differ based on type of prior antimyeloma therapy. Table 8: Trial 1 Results a b POMALYST a (n=108) POMALYST + Low-dose Dex (n=113) Response Overall Response Rate (ORR), b 8 (7. 2) 95% CI for ORR (%) (3. 5) Complete Response (CR), n (%) 0 (0. 9) Partial Response (PR), n (%) 8 (7. 3) Duration of Response (DOR) Median, months NE 7. 4 95% CI for DOR (months) NE (5. 2) Trial 2 Trial 2 was a Phase 3 multi-center, randomized, open-label study, where POMALYST + Low-dose Dex therapy was compared to High-dose Dex in adult patients with relapsed and refractory MM, who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy. Patients with creatinine clearance >= 45mL/min qualified for the trial. A total of 455 patients were enrolled in the trial: 302 in the POMALYST + Low-dose Dex arm and 153 in the High-dose Dex arm. Patients in the POMALYST + Low-dose Dex arm were administered 4 mg POMALYST orally on Days 1 to 21 of each 28-day cycle. Dexamethasone (40 mg) was administered once per day on Days 1, 8, 15 and 22 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. For the High-dose Dex arm, dexamethasone (40 mg) was administered once per day on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Treatment continued until patients had disease progression. Baseline patient and disease characteristics were balanced and comparable between the study arms, as summarized in Table 9. Overall, 94% of patients had disease refractory to lenalidomide, 79% had disease refractory to bortezomib and 74% had disease refractory to both lenalidomide and bortezomib. Table 9: Baseline Demographic and Disease-Related Characteristics en dash Trial 2 Data cutoff: 01March 2013 POMALYST + Low-dose Dex High-dose Dex (N=302) (N=153) Patient Characteristics Median Age, years (range) 64 (35, 84) 65 (35, 87) Age Distribution n (%) < 65 years 158 (52) 74 (48) >= 65 years 144 (48) 79 (52) Sex n (%) Male 181 (60) 87 (57) Female 121 (40) 66 (43) Race/Ethnicity n (%) White 244 (81) 113 (74) Black or African American 4 (1) 3 (2) Asian 4 (1) 0 (0) Other Race 2 (1) 2 (1) Not Collected 48 (16) 35 (23) ECOG Performance n (%) Status 0 110 (36) 36 (24) Status 1 138 (46) 86 (56) Status 2 52 (17) 25 (16) Status 3 0 (0) 3 (2) Missing 2 (1) 3 (2) Disease Characteristics Number of Prior Therapies Median, (Min, Max) 5 (2, 14) 5 (2, 17) Prior stem cell transplant n (%) 214 (71) 105 (69) Refractory to bortezomib and lenalidomide n (%) 225 (75) 113 (74) Table 10 summarizes the progression free survival (PFS) and overall response rate (ORR) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis and overall survival (OS) at the OS analysis. PFS was significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0. 45 (95% CI: 0. OS was also significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0. 70 (95% CI: 0. The Kaplan-Meier curves for PFS and OS for the ITT population are provided in Figures 1 and 2, respectively. Table 10: Trial 2 Results Note: CI=Confidence interval; HD-Dex=High dose dexamethasone; IRAC=Independent Review Adjudication Committee; LD-Dex=Low dose dexamethasone. a b c d e f g POMALYST + Low-dose Dex High-dose Dex (N=302) (N=153) Progression Free Survival Time Number (%) of events 164 (54. 3) Median a 3. 1] Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CI b 0. 59] Log-Rank Test 2-sided P-Value c <0. 001 Overall Survival Time d Number (%) of deaths 147 (48. 2) Median a 12. 0] Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CI e 0. 92] Log-Rank Test 2-sided P-Value f, g 0. 009 Overall Response Rate, n (%) 71 (23. 9) Complete Response 1 (0. 3) 0 Very Good Partial Response 8 (2. 7) Partial Response 62 (20. 3) Figure 1: Progression Free Survival Based on IRAC Review of Response by IMWG Criteria (Stratified Log Rank Test) (ITT Population) Data cut-off: 07 Sep 2012 Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) Data cutoff: 01 Mar 2013 pom-figure-1 pom-figure-2 The clinical trial 12-C-0047 (NCT01495598), was an open label, single center, single arm clinical study that evaluated the safety and efficacy of POMALYST in patients with Kaposi sarcoma (KS). A total of 28 patients (18 HIV-positive, 10 HIV-negative) received POMALYST 5 mg orally once daily on Days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. All HIV-positive patients continued highly active antiretroviral therapy (HAART). The trial excluded patients with symptomatic pulmonary or visceral KS, history of venous or arterial thromboembolism, or procoagulant disorders. Patients received thromboprophylaxis with aspirin 81 mg once daily throughout therapy. The median age was 52. 5 years, all were male, 75% were White, and 14% Black or African American. Seventy-five percent of patients had advanced disease (T1) at the time of enrollment, 11% had >= 50 lesions, and 75% had received prior chemotherapy. The major efficacy outcome measure was overall response rate (ORR), which included complete response (CR), clinical complete response (cCR), and partial response (PR). Response was assessed by the investigator according to the AIDS Clinical Trial Group (ACTG) Oncology Committee response criteria for KS. The median time to first response was 1. 8 months (0. Efficacy results are presented in Table 11. Table 11: Trial 12-C-0047 Results CI: confidence interval, ORR: overall response rate, CR: complete response, PR: partial response 1 2 3 All Patients N=28 HIV-Positive N=18 HIV-Negative N=10 ORR 1 20 (71) 12 (67) 8 (80) [95% CI] [51, 87] (41, 87) (44, 98) CR 1 4 (14) 3 (17) 1 (10) PR, n (%) 16 (57) 9 (50) 7 (70) Duration of Response, KS 2 12. 5 Median in months [95% CI] 3 [7. 2] Duration of Response, KS (%) Percent greater than 12 months 50 58 38 Percent greater than 24 months 20 17 25.
REFERENCES
1. OSHA.

Celgene Corporation

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