Pomalyst

1 INDICATIONS AND USAGE POMALYST is 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. • 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).

1.1Multiple Myeloma 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.

1.2Kaposi Sarcoma

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

2.1Pregnancy Testing Prior to Administration Females

of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST .

2.2Recommended Dosage for Multiple Myeloma 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 .

2.3Recommended Dosage for Kaposi Sarcoma 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) .

2.4Dosage Modifications for Hematologic Adverse Reactions

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. ANC= absolute neutrophil count Neutropenia • 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 POMALYST until ANC is greater than or equal to 500 per mcL; follow CBC weekly. • Resume POMALYST dose at 1 mg less than the previous dose.* • For each subsequent drop of ANC less than 500 per mcL • Withhold POMALYST until ANC is greater than or equal to 500 mcL. • Resume POMALYST dose at 1 mg less than the previous dose.* Thrombocytopenia • Platelets less than 25,000 per mcL • Withhold POMALYST until platelets are greater than or equal to 50,000 per mcL; follow CBC weekly. • Resume POMALYST dose at 1 mg less than the previous dose* • For each subsequent drop of platelets less than 25,000 per mcL • Withhold POMALYST until platelets are greater than or equal to 50,000 per mcL. • Resume POMALYST at 1 mg less than the previous dose* 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. ANC= absolute neutrophil count Neutropenia ANC 500 to less than 1,000 per mcL Day 1 of cycle • Withhold POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at the same dose. During cycle • Continue POMALYST at the current dose.

ANC less than 500 per mcL • Withhold POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at the same dose. Febrile Neutropenia 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 POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at dose 1 mg less than the previous dose.* Thrombocytopenia Platelet count 25,000 to less than 50,000 per mcL Day 1 of cycle • Withhold POMALYST until platelet count is greater than or equal to 50,000 per mcL. • Resume POMALYST at the same dose. During cycle: • Continue POMALYST at the current dose.

Platelet count less than 25,000 per mcL Permanently discontinue POMALYST.

2.5Dosage Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue POMALYST for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction . 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.

2.6Dosage Modifications for Strong CYP1A2 Inhibitors

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 .

2.7Dosage Modification for Severe Renal Impairment

on Hemodialysis Take POMALYST after completion of dialysis procedure on hemodialysis days . • 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.

2.8Dosage 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 . 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 .

2.9Administration Swallow

capsules whole with water. Do not break, chew, or open the capsules. POMALYST may be taken with or without food.

5 WARNINGS AND PRECAUTIONS • Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue. • Hematologic Toxicity: Neutropenia was the most frequently reported Grade 3/4 adverse event. Monitor patients for hematologic toxicities, especially neutropenia. • Hepatotoxicity: Hepatic failure including fatalities; monitor liver function tests monthly. • Severe Cutaneous Reactions: Discontinue POMALYST for severe reactions. • Tumor Lysis Syndrome (TLS): Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions. • Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue POMALYST for angioedema and anaphylaxis.

5.1Embryo-Fetal Toxicity

POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death . POMALYST is only available through PS-Pomalidomide REMS . Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning POMALYST 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 POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST 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 . 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 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 . Blood Donation Patients must not donate blood during treatment with POMALYST 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 POMALYST.

5.2PS-Pomalidomide

REMS Because of the embryo-fetal risk , POMALYST is 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 and males must comply with contraception requirements . • Pharmacies must be certified with PS-Pomalidomide REMS , must only dispense to patients who are authorized to receive POMALYST 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.

5.3Venous 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 POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST 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 POMALYST 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 POMALYST 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.

5.4Increased 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.

5.5Hematologic Toxicity Multiple Myeloma In

trials 1 and 2 in patients who received POMALYST + 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 . Kaposi Sarcoma In Trial 12-C-0047, hematologic toxicities were the most common (all grades and Grade 3 or 4) adverse reactions . 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 POMALYST based on the severity of the reaction .

5.6Hepatotoxicity Hepatic

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

5.7Severe 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 POMALYST interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue POMALYST for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS .

5.8Dizziness and Confusional State In

trials 1 and 2 in patients who received POMALYST + 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.

5.9Neuropathy In

trials 1 and 2 in patients who received POMALYST + 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.

5.10Risk of Second Primary Malignancies Cases

of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of MM.

5.11Tumor Lysis Syndrome Tumor

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

5.12Hypersensitivity Hypersensitivity,

including angioedema, anaphylaxis, and anaphylactic reactions to POMALYST have been reported. Permanently discontinue POMALYST for angioedema or anaphylaxis .

4 CONTRAINDICATIONS • Pregnancy • Hypersensitivity

4.1Pregnancy

POMALYST is contraindicated in females who are pregnant. POMALYST can cause fetal harm when administered to a pregnant female . 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.

4.2Hypersensitivity

POMALYST is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients .

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action and findings from animal studies, POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy . POMALYST is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis.

Pomalidomide crossed the placenta after administration to pregnant rabbits . If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels.

There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses.

In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals.

No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption. Following daily oral administration of pomalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma pomalidomide concentrations were approximately 50% of the maternal C max at all dosages (5 to 250 mg/kg/day), indicating that pomalidomide crossed the placenta.

The following clinically significant adverse reactions are described in detail in other labeling sections: • Embryo-Fetal Toxicity • Venous and Arterial Thromboembolism • Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone • Hematologic Toxicity • Hepatotoxicity • Severe Cutaneous Reactions • Dizziness and Confusional State • Neuropathy • Risk of Second Primary Malignancies • Tumor Lysis Syndrome • Hypersensitivity • MM: Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia. • 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. To report SUSPECTED ADVERSE REACTIONS, contact Bristol Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Multiple Myeloma (MM) In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5.

Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%. In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with POMALYST + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients).

The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5. In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks.

Eight percent of patients discontinued POMALYST due to adverse reactions. Tables 3 and 4 summarize the adverse reactions reported in Trials 1 and 2, respectively. Table 3: Adverse Reactions in Any POMALYST Treatment Arm in Trial 1* * Regardless of attribution of relatedness to POMALYST. a POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any POMALYST treatment arm.

Data cutoff: 01 March 2013 All Adverse Reactions ≥10% in Either Arm Grade 3 or 4 ≥5% in Either Arm Body System Adverse Reaction POMALYST a (N=107) POMALYST + Low-dose Dex (N=112) POMALYST (N=107) POMALYST + Low-dose Dex (N=112) Number (%) of patients with at least one adverse reaction 107 112 98 102 Blood and lymphatic system disorders Neutropenia b 57 55 51 46 Anemia b 41 47 25 24 Thrombocytopenia b 28 26 24 21 Leukopenia 14 22 7 11 Febrile neutropenia b <10% <10% 6 3 Lymphopenia 4 17 2 8 General disorders and administration site conditions Fatigue and asthenia b 62 70 13 19 Edema peripheral 27 19 0 0 Pyrexia b 25 36 <5% <5% Chills 11 14 0 0 Gastrointestinal disorders Nausea b 39 27 <5% <5% Constipation b 38 41 <5% <5% Diarrhea 37 40 <5% <5% Vomiting b 15 16 <5% 0 Musculoskeletal and connective tissue disorders Back pain b 37 36 15 11 Musculoskeletal chest pain 25 22 <5% 0 Muscle spasms 23 22 <5% <5% Arthralgia 18 17 <5% <5% Muscular weakness 15 15 6 4 Bone pain 13 8 <5% <5% Musculoskeletal pain 13 19 <5% <5% Pain in extremity 8 16 0 <5% Infections and infestations Upper respiratory tract infection 40 32 <5% <5% Pneumonia b 30 38 21 32 Urinary tract infection b 11 19 2 10 Sepsis b <10% <10% 6 5 Metabolism and nutrition disorders Decreased appetite 25 21 <5% 0 Hypercalcemia b 23 13 11 1 (<1) Hypokalemia 13 13 <5% <5% Hyperglycemia 12 17 <5% <5% Hyponatremia 12 14 <5% <5% Dehydration b <10% <10% 5 6 Hypocalcemia 6 13 0 <5% Respiratory, thoracic and mediastinal disorders Dyspnea b 38 50 8 14 Cough 18 25 0 0 Epistaxis 18 12 <5% 0 Productive cough 10 14 0 0 Oropharyngeal pain 6 12 0 0 Nervous system disorders Dizziness 24 20 <5% <5% Peripheral neuropathy 23 20 0 0 Headache 16 15 0 <5% Tremor 11 15 0 0 Skin and subcutaneous tissue disorders Rash 22 18 0 <5% Pruritus 16 10 0 0 Dry skin 10 12 0 0 Hyperhidrosis 8 18 0 0 Night sweats 5 14 0 0 Investigations Blood creatinine increased b 20 11 6 3 Weight decreased 16 10 0 0 Weight increased 1 (<1) 12 0 0 Psychiatric disorders Anxiety 14 8 0 0 Confusional state b 13 15 6 3 Insomnia 7 18 0 0 Renal and urinary disorders Renal failure b 16 11 9 8 Table 4: Adverse Reactions in Trial 2 a Percentage did not meet the criteria to be considered as an adverse reaction for POMALYST for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013 All Adverse Reactions (≥5% in POMALYST + Low-dose Dex arm, and at least 2% higher than the High-dose-Dex arm) Grade 3 or 4 (≥1% in POMALYST + Low-dose Dex arm, and at least 1% higher than the High-dose-Dex arm) Body System Adverse Reaction POMALYST + Low-dose Dex (N=300) High-dose Dex (N=150) POMALYST + Low-dose Dex (N=300) High-dose Dex (N=150) Number (%) of patients with at least one adverse reaction 297 149 259 127 Blood and lymphatic system disorders Neutropenia b 154 31 145 24 Thrombocytopenia 89 a 44 a 66 a 39 a Leukopenia 38 8 27 5 Febrile neutropenia b 28 0 28 0 General disorders and administration site conditions Fatigue and asthenia 140 64 26 a 18 a Pyrexia b 80 35 9 a 7 a Edema peripheral 52 17 4 a 3 a Pain 11 a 3 a 5 1 (<1) Infections and infestations Upper respiratory tract infection b 93 19 9 1 (<1) Pneumonia b 58 20 47 15 Neutropenic sepsis b 3 a 0 a 3 0 Gastrointestinal disorders Diarrhea 66 28 3 a 2 a Constipation 65 22 7 0 Nausea 45 17 3 a 2 a Vomiting 23 6 3 0 Musculoskeletal and connective tissue disorders Back pain b 59 24 15 6 Bone pain b 54 21 22 7 Muscle spasms 46 11 1 (<1) a 1 (<1) a Arthralgia 26 7 2 (<1) a 1 (<1) a Pain in extremity 20 a 9 a 6 0 Respiratory, thoracic and mediastinal disorders Dyspnea b 76 25 17 7 Cough 60 15 2 (<1) a 1 (<1) a Chronic obstructive pulmonary disease b 5 a 0 a 4 0 Nervous system disorders Peripheral neuropathy 52 18 5 a 2 a Dizziness 37 14 4 a 2 a Headache 23 8 1 (<1) a 0 a Tremor 17 2 2 (<1) a 0 a Depressed level of consciousness 5 a 0 a 3 0 Metabolism and nutrition disorders Decreased appetite 38 12 3 a 2 a Hypokalemia 28 a 12 a 12 4 Hypocalcemia 12 a 9 a 5 1 (<1) Skin and subcutaneous tissue disorders Rash 23 2 3 0 Pruritus 22 5 0 a 0 a Hyperhidrosis 15 1 (<1) 0 a 0 a Investigations Neutrophil count decreased 15 1 (<1) 14 1 (<1) Platelet count decreased 10 a 3 a 8 2 White blood cell count decreased 8 a 1 (<1) a 8 0 Alanine aminotransferase increased 7 a 2 a 5 0 Aspartate aminotransferase increased 4 a 2 a 3 0 Lymphocyte count decreased 3 a 1 (<1) a 3 0 Renal and urinary disorders Renal failure 31 a 18 a 19 8 Injury, poisoning and procedural complications Femur fracture b 5 a 1 (<1) a 5 1 (<1) Reproductive system and breast disorders Pelvic pain 6 a 3 a 4 0 Other Adverse Reactions Other adverse reactions of POMALYST in patients with MM, not described above, and considered important: Cardiac Disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and Labyrinth Disorders: Vertigo Gastrointestinal disorders: Abdominal pain General Disorders and Administration Site Conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary Disorders: Hyperbilirubinemia Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection Investigations: Alanine aminotransferase increased, Hemoglobin decreased Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous system disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension Kaposi Sarcoma (KS) The safety of POMALYST in patients with KS was evaluated in Trial 12-C-0047 . Twenty-eight patients received POMALYST 5 mg taken orally once daily on Days 1 through 21 of repeated 28-day cycles. The study excluded patients with procoagulant disorders or a history of venous or arterial thromboembolism.

Patients received DVT prophylaxis with daily low dose aspirin. Across all patients treated on Trial 12-C-0047, 75% were exposed to pomalidomide for 6 months or longer and 25% were exposed for greater than one year. Serious adverse reactions occurred in 18% (5/28) of patients who received POMALYST. The following serious adverse reactions each occurred in 1 patient: anemia, decreased neutrophil count, and hematuria.

Permanent discontinuation due to an adverse reaction occurred in 11% (3/28) of patients who received POMALYST. Dosage interruptions due to an adverse reaction occurred in 14% (4/28) of patients who received POMALYST. The most frequent adverse reaction requiring dosage interruption was decreased neutrophil count, which occurred in 3 patients. The POMALYST dose was reduced due to an adverse reaction in 1 patient due to gout. Tables 5 and 6 summarize the adverse reactions and select laboratory abnormalities reported in Trial 12-C-0047.

Table 5: Adverse Reactions (≥ 20%) in Patients Who Received POMALYST in Trial 12-C-0047 Adverse Reaction Grades 1-4 N=28 % Grade 3 or 4 N=28 % Rash, maculo-papular 71

3.6Constipation

71 0 Fatigue 68 0 Nausea 36 0 Diarrhea 32

3.6Cough

29 0 Dyspnea 29 0 Peripheral Edema 29

3.6Upper

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

3.6Decreased Hemoglobin

54 0 Decreased Platelets 54 0 Chemistry Elevated Creatinine 86

3.6Elevated Glucose

57 7 Decreased Albumin 54 0 Decreased Phosphate 54 25 Decreased Calcium 50 0 Increased Alanine Aminotransferase (ALT) 32 0 Increased Aspartate Aminotransferase (AST) 25 0 Elevated Creatine Kinase 25 7 Decreased Magnesium 14 0 Elevated Alkaline Phosphate 14 3.6

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval use of POMALYST. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Pancytopenia Endocrine Disorders: Hypothyroidism, hyperthyroidism Gastrointestinal Disorders: Gastrointestinal hemorrhage Hepatobiliary Disorders: Hepatic failure (including fatal cases), elevated liver enzymes Immune system Disorders: Allergic reactions (e.g., angioedema, anaphylaxis, urticaria), solid organ transplant rejection Infections and Infestations: Hepatitis B virus reactivation, Herpes zoster, progressive multifocal leukoencephalopathy (PML) Neoplasms benign, malignant and unspecified (incl cysts and polyps): Tumor lysis syndrome, basal cell carcinoma, and squamous cell carcinoma of the skin Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)