POMALIDOMIDE: 92,291 Adverse Event Reports & Safety Profile

Pomalidomide is a thalidomide analog. The chemical name is ( RS )-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure: The empirical formula for pomalidomide is C 13 H 11 N 3 O 4 and the gram molecular weight is 273.25. Pomalidomide is a light yellow to yellow colored powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers. Pomalidomide capsules are available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, croscarmellose sodium and sodium stearyl fumarate.

The

1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink.

The

2-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, iron oxide yellow, FD&C Red #3, and white ink.

The

3-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, iron oxide yellow, and white ink.

The

4-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, and white ink. Black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water. White ink contains Shellac, ethanol, isopropyl alcohol, n-butanol, propylene glycol, ammonia solution, purified water, potassium hydroxide, and titanium dioxide. structure

AND USAGE Pomalidomide capsules are a thalidomide analogue indicated for the treatment of adult patients: in combination with dexamethasone, for 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 ( 1.1 ). with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) ( 1.2 ).

1.1 Multiple Myeloma Pomalidomide, in combination with dexamethasone, are 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.

1.2 Kaposi Sarcoma Pomalidomide capsules are indicated for the treatment of: Adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART). Kaposi sarcoma (KS) in adult patients who are HIV-negative. This indication is approved under accelerated approval based on overall response rate <span class="opacity-50 text-xs">[see Clinical Studies (14.2 )]</span>. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

AND ADMINISTRATION MM: 4 mg per day taken orally on Days 1 through 21 of repeated 28-­day cycles until disease progression (2.2). Refer to section 14.1 for dexamethasone dosing (14.1) . KS: 5 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression or unacceptable toxicity (2.3) . Modify the dosage for certain patients with renal impairment (2.7, 8.6) or hepatic impairment (2.8, 8.7) .

2.1 Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating pomalidomide capsules <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.3) ]</span>.

2.2 Recommended Dosage for Multiple Myeloma The recommended dosage of pomalidomide capsules is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give pomalidomide capsules in combination with dexamethasone <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

2.3 Recommended Dosage for Kaposi Sarcoma The recommended dosage of pomalidomide capsules 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) <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> .

2.4 Dosage Modifications for Hematologic Adverse Reactions Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules 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 pomalidomide capsules for hematologic adverse reactions in patients with MM are summarized in Table 1.

Table

1: Dosage Modifications for Pomalidomide Capsules for Hematologic in MM * Permanently discontinue pomalidomide capsules if unable to tolerate 1 mg once daily. ANC= absolute neutrophil count Adverse Reaction Severity Dosage Modification Neutropenia [see Warnings and Precautions (5.5)] ANC less than 500 per mcL or febrile neutropenia (fever greater than or equal to 38.5°C and ANC less than 1,000 per mcL) Withhold pomalidomide capsules until ANC is greater than or equal to 500 per mcL; follow CBC weekly. Resume pomalidomide capsules dose at 1 mg less than the previous dose.* For each subsequent drop of ANC less than 500 per mcL Withhold pomalidomide capsules until ANC is greater than or equal to 500 mcL. Resume pomalidomide capsules dose at 1 mg less than the previous dose.* Thrombocytopenia [see Warnings and Precautions (5.5)] Platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per mcL; follow CBC weekly. Resume pomalidomide capsules dose at 1 mg less than the previous dose* For each subsequent drop of platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per mcL. Resume pomalidomide capsules at 1 mg less than the previous dose* Kaposi Sarcoma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules 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 pomalidomide capsules for hematologic adverse reactions in patients with KS are summarized in Table 2.

Table

2: Dosage Modifications for Pomalidomide Capsules for Hematologic Adverse Reactions in KS * Permanently discontinue pomalidomide capsules if unable to tolerate 1mg once daily. ANC= absolute neutrophil count Adverse Reaction Severity Dosage Modification Neutropenia [see Warnings and Precautions (5.5) ] ANC 500 to less than 1,000 per mcL Day 1 of cycle Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL. Resume pomalidomide capsules at the same dose. During cycle Continue pomalidomide capsules at the current dose. ANC less than 500 per mcL Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL. Resume pomalidomide capsules at the same dose.

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 ᵒ C or ANC less than 1,000 per mcL and sustained temperature greater than or equal to 38 ᵒ C for more than 1 hour Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL. Resume pomalidomide capsules at dose 1 mg less than the previous dose.* Thrombocytopenia [see Warnings and Precautions (5.5) ] Platelet count 25,000 to less than 50,000 per mcL Day 1 of cycle Withhold pomalidomide capsules until platelet count is greater than or equal to 50,000 per mcL. Resume pomalidomide capsules at the same dose. During cycle: Continue pomalidomide capsules at the current dose. Platelet count less than 25,000 per mcL Permanently discontinue pomalidomide capsules.

2.5 Dosage Modifications for Non-Hematologic Adverse Reactions Permanently discontinue pomalidomide capsules for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction [See Warnings and Precautions (5.7 , 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.

2.6 Dosage Modifications for Strong CYP1A2 Inhibitors Avoid concomitant use of pomalidomide capsules with strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce pomalidomide capsules dose to 2 mg <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]</span> .

2.7 Dosage Modification for Severe Renal Impairment on Hemodialysis Take pomalidomide capsules after completion of dialysis procedure on hemodialysis days <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> . For patients with MM with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily. For patients with KS with severe renal impairment requiring dialysis, reduce the recommended dosage to 4 mg orally daily.

2.8 Dosage Modification for Hepatic Impairment 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> .

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 (8.7) and Clinical Pharmacology (12.3) ] .

2.9 Administration Swallow capsules whole with water. Do not break, chew, or open the capsules. Pomalidomide capsules may be taken with or without food.

Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 )

4.1 Pregnancy Pomalidomide capsules are contraindicated in females who are pregnant. Pomalidomide capsules can cause fetal harm when administered to a pregnant female <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 )]</span>. 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 Pomalidomide Capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7 ), Description (11) ]</span>.

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 )]. 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 Breckenridge Pharmaceutical Inc. at 1-800-367-3395 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 Pomalidomide + Low-dose Dex (112 patients) or pomalidomide 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 Pomalidomide + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the Pomalidomide + Low-dose Dex arm was 5. In the Pomalidomide + Low-dose Dex arm, 67% of patients had a dose interruption of pomalidomide capsules, the median time to the first dose interruption of pomalidomide was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of pomalidomide, the median time to the first dose reduction of pomalidomide was 4.5 weeks. Eight percent of patients discontinued pomalidomide 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 Pomalidomide Capsules Treatment Arm in Trial 1* * Regardless of attribution of relatedness to pomalidomide. a Pomalidomide alone arm includes all patients randomized to the pomalidomide 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 pomalidomide 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 Pomalidomide a (N=107) Pomalidomide + Low-dose Dex (N=112) Pomalidomide (N=107) Pomalidomide + 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 All Adverse Reactions (≥5% in Pomalidomide + Low-dose Dex arm, and at least 2% higher than the High-dose-Dex arm)

Grade

3 or 4 (≥1% in Pomalidomide + Low-dose Dex arm, and at least 1% higher than the High-dose-Dex arm)

Body System Adverse Reaction

Pomalidomide + Low-dose Dex (N=300) High- dose Dex (N=150) Pomalidomide + 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) a Percentage did not meet the criteria to be considered as an adverse reaction for pomalidomide 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 Other Adverse Reactions Other adverse reactions of pomalidomide capsules 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 pomalidomide capsules in patients with KS was evaluated in Trial 12-C-0047 [see Clinical Studies (14.2 )]. Twenty-eight patients received pomalidomide capsules 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 pomalidomide capsules. 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 pomalidomide capsules. Dosage interruptions due to an adverse reaction occurred in 14% (4/28) of patients who received pomalidomide capsules. The most frequent adverse reaction requiring dosage interruption was decreased neutrophil count, which occurred in 3 patients. The pomalidomide capsules 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 Pomalidomide Capsules 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 Pomalidomide Capsules in Trial 12-C-0047 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 * Denominator is the number of patients for whom there is a baseline and at least one post baseline assessment for the laboratory parameter.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of pomalidomide capsules. 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)

AND PRECAUTIONS Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.4 ).

Hematologic

Toxicity: Neutropenia was the most frequently reported Grade 3/4 adverse event. Monitor patients for hematologic toxicities, especially neutropenia ( 5.5 ). Hepatotoxicity: Hepatic failure including fatalities; monitor liver function tests monthly ( 5.6 ).

Severe Cutaneous

Reactions: Discontinue pomalidomide capsules for severe reactions ( 5.7 ).

Tumor Lysis

Syndrome (TLS): Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.11 ). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue pomalidomide capsules for angioedema and anaphylaxis ( 5.12 ).

5.1 Embryo-Fetal Toxicity Pomalidomide capsules are a thalidomide analogue and are contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>. Pomalidomide capsules are only available through PS-Pomalidomide REMS <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2 )]</span>. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning Pomalidomide Capsules therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with pomalidomide capsules, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of pomalidomide capsules therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing pomalidomide capsules therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles, or every 2 weeks in females with irregular menstrual cycles <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3 )]</span>.

Males

Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking pomalidomide capsules and for up to 4 weeks after discontinuing pomalidomide capsules, even if they have undergone a successful vasectomy. Male patients taking pomalidomide capsules must not donate sperm [see Use in Specific Populations (8.3) ].

Blood Donation

Patients must not donate blood during treatment with pomalidomide capsules and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to pomalidomide capsules.

5.2 PS-Pomalidomide REMS Because of the embryo-fetal risk <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>, pomalidomide capsules are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), “PS-Pomalidomide REMS”. Required components of PS-Pomalidomide REMS include the following: Prescribers must be certified with PS-Pomalidomide REMS by enrolling and complying with the REMS requirements. Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> and males must comply with contraception requirements <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span>. Pharmacies must be certified with PS-Pomalidomide REMS, must only dispense to patients who are authorized to receive pomalidomide capsules and comply with REMS requirements. Further information about PS-Pomalidomide REMS is available at www.PS-PomalidomideREMS.com or by telephone at 1-888-423-5436.

5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with pomalidomide capsules.

In Trial

2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with pomalidomide capsules and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with pomalidomide capsules and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with pomalidomide capsules and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors.

5.4 Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.5 Hematologic Toxicity Multiple Myeloma In trials 1 and 2 in patients who received pomalidomide + Low-dose Dex, neutropenia was the most frequently reported Grade 3 or 4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3 or 4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

Kaposi Sarcoma In Trial

12-C-0047, hematologic toxicities were the most common (all grades and Grade 3 or 4) adverse reactions [see Adverse Reactions (6.1) ]. Fifty percent of patients had Grade 3 or 4 neutropenia. Monitor patients for hematologic toxicities, especially decreased neutrophils. Monitor complete blood counts every 2 weeks for the first 12 weeks and monthly thereafter. Withhold, reduce the dose, or permanently discontinue pomalidomide based on the severity of the reaction [see Dosage and Administration (2.4) ].

5.6 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with pomalidomide capsules. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with pomalidomide capsules. Monitor liver function tests monthly. Stop pomalidomide capsules upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered.

5.7 Severe Cutaneous Reactions Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Consider pomalidomide capsules interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue pomalidomide capsules for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

5.8 Dizziness and Confusional State In trials 1 and 2 in patients who received pomalidomide capsules + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

5.9 Neuropathy In trials 1 and 2 in patients who received pomalidomide capsules + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial.

5.10 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving pomalidomide capsules as an investigational therapy outside of MM.

5.11 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.12 Hypersensitivity Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to pomalidomide capsules have been reported. Permanently discontinue pomalidomide capsules for angioedema or anaphylaxis <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

INTERACTIONS Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce pomalidomide capsules dose to 2 mg ( 2.6 , 7.1 , 12.3 ).

7.1 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3 )]</span>. 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 pomalidomide capsules dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.6 )]</span>.