Pomalidomide

12.1 Mechanism of Action 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.g., TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

1 INDICATIONS 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 [see Clinical Studies (14.2 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3 )]. 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 [see Clinical Studies (14.1 )]. 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) [see Clinical Studies (14.2)]. 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. * Thrombocytopenia [see Warnings and Precautions (5.5) ] 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. * 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 than1,000 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°C or ANC less than 1,000 per mcL and sustained temperature greater than or equal to 38°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 Dosag

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other labeling sections: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1, 5.2 )] Venous and Arterial Thromboembolism [ see Warnings and Precautions (5.3) ] Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.4) ] Hematologic Toxicity [see Warnings and Precautions (5.5) ] Hepatotoxicity [see Warnings and Precautions (5.6) ] Severe Cutaneous Reactions [see Warnings and Precautions (5.7)] Dizziness and Confusional State [see Warnings and Precautions (5.8 )] Neuropathy [see Warnings and Precautions (5.9 )] Risk of Second Primary Malignancies [see Warnings and Precautions (5.10 )] Tumor Lysis Syndrome [see Warnings and Precautions (5.11 )] Hypersensitivity [see Warnings and Precautions (5.12 )]. 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

7 DRUG 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 [see Clinical Pharmacology (12.3 )]. 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 [see Dosage and Administration (2.6 )].