Coming. Available Spring Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, New Jersey U.S.A.

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1 Coming s n Available Spring 215 Novo Nordisk Inc., 8 Scudders Mill Road, Plainsboro, New Jersey 8536 U.S.A. Novoeight is a registered trademark of Novo Nordisk Health Care AG. 215 Novo Nordisk All rights reserved January 215

2 THERE S A INSIDE EVERYONE WITH THE POTENTIAL TO TAKE ON MULTIPLE MYELOMA

3 Despite recent advances, multiple myeloma remains a largely incurable disease, with fewer than half of patients surviving f ve years after diagnosis. 1 Natural killer cells are part of the body s f rst line of defense against cancer, but myeloma cells evade and suppress a patient s natural immune response, making further medical advances challenging We need a new approach. Bristol-Myers Squibb is deeply committed to furthering the science behind Immuno-Oncology. Leading the way in Immuno-Oncology research, Bristol-Myers Squibb is investigating the potential of the SLAMF7, KIR, and CD137 pathways to activate the body s own natural killer cells to target myeloma cells. REFERENCES: 1. SEER Stat Fact Sheets: Myeloma, Accessed July 17, 214; 2. Godfrey J and Benson DM Jr. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 212;53: ; 3. Cheng M, Chen Y, Xiao W et al. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 213;1:23-252; 4. Bernal M, Garrido P, Jiménez P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma : implications for tumor evasion of T and NK cells. Human Immunol. 29;7: ; 5. Jinushi M, Vanneman M, Munshi NC et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 28;15: ; 6. Carbone E, Neri P, Mesuraca M et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 25;15: ; 7. von Lilienfeld-Toal M, Frank S, Leyendecker C et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 21;59: ; 8. Cook G, Campbell JDM, Carr CE et al. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66: ; 9. Yu J, Wei M, Becknell B et al. Pro- and anti-infl ammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 26;24:575-59; 1. Nielsen H, Nielsen HJ, Tvede N et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99:34-346; 11. Tinhofer I, Marschitz I, Henn T et al. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2;95: Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB /14

4 The only offcial 215 Highlights of ASH in Latin America April 23-24, 215 Hotel Las Americas Resort, Spa, and Convention Center Cartagena, Colombia The most signifcant scientifc and educational updates from the 56th ASH Annual Meeting are coming to Latin America. Get a synopsis of the top hematology research presented and learn how it can help translate into and improve your patient management and care strategies. Examine advances in clinical and translational hematologic research Evaluate the role of new diagnostic techniques and therapeutic approaches as applied to the care and management of people with blood diseases Discuss new patient management and care strategies and emerging drug therapies with leading faculty in the feld Check the website for updates and to register at CME Credits This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society of Hematology and the Asociación Colombiana de Hematología y Oncología. The American Society of Hematology is accredited by the ACCME to provide continuing medical education for physicians. The American Society of Hematology designates this live educational activity for a maximum of 9.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

5 XARELTO (rivaroxaban) tablets Table 1: Bleeding Events in ROCKET AF* Parameter XARELTO N = 7111 n Event Rate (per 1 Pt-yrs) Warfarin N = 7125 n Event Rate (per 1 Pt-yrs) Major bleeding 395 (5.6) (5.4) 3.5 Bleeding into a critical organ 91 (1.3) (1.9) 1.2 Fatal bleeding 27 (.4).2 55 (.8).5 Bleeding resulting in 183 (2.6) (2.1) 1.3 transfusion of 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) (2.) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. Defned as clinically overt bleeding associated with a decrease in hemoglobin of 2 g/dl, transfusion of 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and effcacy events. Major bleeding rates excluding strokes are 3.3 per 1 Pt-yrs for XARELTO vs. 2.9 per 1 Pt-yrs for warfarin. The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE: EINSTEIN DVT and EINSTEIN PE Studies: In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 28 days for XARELTOtreated patients and 24 days for enoxaparin/vka-treated patients. Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter XARELTO N = 413 n Enoxaparin/VKA N = 4116 n Major bleeding event 4 (1.) 72 (1.7) Fatal bleeding 3 (<.1) 8 (.2) Intracranial 2 (<.1) 4 (<.1) Non-fatal critical organ bleeding 1 (.2) 29 (.7) Intracranial 3 (<.1) 1 (.2) Retroperitoneal 1 (<.1) 8 (.2) Intraocular 3 (<.1) 2 (<.1) Intra-articular 4 (<.1) Non-fatal non-critical organ bleeding 27 (.7) 37 (.9) Decrease in Hb 2g/dL 28 (.7) 42 (1.) Transfusion of 2 units of whole blood or packed 18 (.4) 25 (.6) red blood cells Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 2 mg once daily; enoxaparin/vka [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.-3.)] Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb 2 g/dl and/or transfusion of 2 units of whole blood or packed red blood cells EINSTEIN Extension Study: In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs..2% for placebo treatment groups. The mean duration of treatment was 19 days for both XARELTO and placebo treatment groups. Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study. Table 3: Bleeding Events* in EINSTEIN Extension Study Parameter XARELTO 2 mg N = 598 n Placebo N = 59 n Major bleeding event 4 (.7) Decrease in Hb 2 g/dl 4 (.7) Transfusion of 2 units of whole blood or 2 (.3) packed red blood cells Gastrointestinal 3 (.5) Menorrhagia 1 (.2) Clinically relevant non-major bleeding 32 (5.4) 7 (1.2) Any bleeding 14 (17.4) 63 (1.7) * Bleeding event occurred after the frst dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. Treatment schedule: XARELTO 2 mg once daily; matched placebo once daily There were no fatal or critical organ bleeding events. XARELTO (rivaroxaban) tablets Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4. Table 4: Bleeding Events * in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) XARELTO 1 mg Enoxaparin Total treated patients N = 4487 n N = 4524 n Major bleeding event 14 (.3) 9 (.2) Fatal bleeding 1 (<.1) Bleeding into a critical organ 2 (<.1) 3 (.1) Bleeding that required re-operation 7 (.2) 5 (.1) Extra-surgical site bleeding requiring 4 (.1) 1 (<.1) transfusion of >2 units of whole blood or packed cells Any bleeding event 261 (5.8) 251 (5.6) Hip Surgery Studies N = 3281 n N = 3298 n Major bleeding event 7 (.2) 3 (.1) Fatal bleeding 1 (<.1) Bleeding into a critical organ 1 (<.1) 1 (<.1) Bleeding that required re-operation 2 (.1) 1 (<.1) Extra-surgical site bleeding requiring 3 (.1) 1 (<.1) transfusion of >2 units of whole blood or packed cells Any bleeding event 21 (6.1) 191 (5.8) Knee Surgery Study N = 126 n N = 1226 n Major bleeding event 7 (.6) 6 (.5) Fatal bleeding Bleeding into a critical organ 1 (.1) 2 (.2) Bleeding that required re-operation 5 (.4) 4 (.3) Extra-surgical site bleeding requiring 1 (.1) transfusion of >2 units of whole blood or packed cells Any bleeding event 6 (5.) 6 (4.9) * Bleeding events occurring any time following the frst dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 4 mg once daily (RECORD 1-3) Includes major bleeding events Following XARELTO treatment, the majority of major bleeding complications ( 6%) occurred during the frst week after surgery. Other Adverse Reactions: Non-hemorrhagic adverse reactions reported in 1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5. Table 5: Other Adverse Reactions * Reported by 1% of XARELTO-Treated Patients in EINSTEIN Extension Study System Organ Class Preferred Term Gastrointestinal XARELTO N = 598 n Placebo N = 59 n Abdominal pain upper 1 (1.7) 1 (.2) Dyspepsia 8 (1.3) 4 (.7) Toothache 6 (1.) General and administration site conditions Fatigue 6 (1.) 3 (.5) Infections and infestations Sinusitis 7 (1.2) 3 (.5) Urinary tract infection 7 (1.2) 3 (.5) Musculoskeletal and connective tissue Back pain 22 (3.7) 7 (1.2) Osteoarthritis 1 (1.7) 5 (.8) Respiratory, thoracic and mediastinal Oropharyngeal pain 6 (1.) 2 (.3) * Adverse reaction (with Relative Risk >1.5 for XARELTO versus placebo) occurred after the frst dose and up to 2 days after the last dose of study drug. Incidences are based on the number of patients, not the number of events. Although a patient may have had 2 or more clinical adverse reactions, the patient is counted only once in a category. The same patient may appear in different categories. Non-hemorrhagic adverse reactions reported in 1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 6.

6 XARELTO (rivaroxaban) tablets Table 6: Other Adverse Drug Reactions * Reported by 1% of XARELTO-Treated Patients in RECORD 1-3 Studies System/Organ Class Adverse Reaction XARELTO 1 mg N = 4487 n Enoxaparin N = 4524 n Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.) Musculoskeletal and connective tissue Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (.7) Nervous system Syncope 55 (1.2) 32 (.7) Skin and subcutaneous tissue Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 4 (.9) * Adverse reaction occurring any time following the frst dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 4 mg once daily (RECORD 1-3) Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 1 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Postmarketing Experience: The following adverse reactions have been identifed during post-approval use of rivaroxaban. 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 : agranulocytosis Gastrointestinal : retroperitoneal hemorrhage Hepatobiliary : jaundice, cholestasis, cytolytic hepatitis Immune system : hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system : cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue : Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP45 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure. Drugs that Inhibit Cytochrome P45 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and fuconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 3% to 16%. Signifcant increases in rivaroxaban exposure may increase bleeding risk [see Clinical Pharmacology (12.3) in full Prescribing Information]. When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors. Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors [see Warnings and Precautions]. Drugs that Induce Cytochrome P45 3A4 Enzymes and Drug Transport Systems: Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of XARELTO with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 5%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease effcacy [see Clinical Pharmacology (12.3) in full Prescribing Information]. Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John s wort) [see Warnings and Precautions]. Anticoagulants and NSAIDs/Aspirin: Single doses of enoxaparin and XARELTO given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO resulted in an additive effect on factor Xa (FXa) inhibition and PT. Concomitant aspirin use has been identifed as an independent risk factor for major bleeding in effcacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Coadministration of the platelet aggregation inhibitor clopidogrel and XARELTO resulted in an increase in bleeding time for some subjects [see Clinical Pharmacology (12.3) in full Prescribing Information]. Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless beneft outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions]. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P45 3A4 Enzymes and Drug Transport Systems: Results from a pharmacokinetic trial with erythromycin indicated that patients with renal impairment coadministered XARELTO with drugs classifed as combined P-gp and moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and erythromycin) have increased exposure compared with patients with normal renal function and no inhibitor use. Signifcant increases in rivaroxaban exposure may increase bleeding risk. While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 3 to <5 ml/min [Hazard Ratio (95% CI): 1.5 (.77, 1.42)] [see Use in Specifc Populations]. XARELTO should not be used in patients with CrCl 15 to 8 ml/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors unless the potential beneft justifes the potential risk [see Clinical Pharmacology (12.3) in full Prescribing Information]. XARELTO (rivaroxaban) tablets USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential beneft justifes the potential risk to mother and fetus [see Warnings and Precautions]. Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of 1 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 2 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 12 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug. Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 4 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 2 mg/day). Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/ or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the effcacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-beneft profle was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information]. Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. Renal Impairment: In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in full Prescribing Information]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 3 to 5 ml/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 2 mg once daily. Patients with CrCl 15 to 3 ml/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3) in full Prescribing Information]. Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE: In the EINSTEIN trials, patients with CrCl values <3 ml/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <3 ml/min. Prophylaxis of DVT Following Hip or Knee Replacement Surgery: The combined analysis of the RECORD 1-3 clinical effcacy studies did not show an increase in bleeding risk for patients with CrCl 3 to 5 ml/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 3 to 5 ml/min. Avoid the use of XARELTO in patients with CrCl <3 ml/min. Hepatic Impairment: In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in full Prescribing Information]. Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child- Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. OVERDOSAGE: Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specifc antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >5 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 778 or Bayer Pharma AG Leverkusen, Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 856 Licensed from: Bayer HealthCare AG Leverkusen, Germany Janssen Pharmaceuticals, Inc

7 DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefi t-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fi brillation and atrial fl utter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fi brillation. Periodically monitor patients clinically for atrial fi brillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or newonset dyspnea should have an ECG performed. If atrial fi brillation persists, consider the risks and benefi ts of IMBRUVICA treatment and dose modifi cation. Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

8 IMBRUVICA (ibrutinib) is the frst and only FDA-approved therapy for use in patients with Waldenström s macroglobulinemia (WM) IMBRUVICA is approved for use in 4 indications IMBRUVICA is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verifcation of clinical beneft in confrmatory trials. Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Chronic lymphocytic leukemia with 17p deletion. Waldenström s macroglobulinemia (WM). Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity - Based on fndings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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 hazard to a fetus. ADVERSE REACTIONS The most common adverse reactions ( 25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Seven percent of patients receiving IMBRUVICA discontinued treatment due to adverse events. DRUG INTERACTIONS CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose. Please review the Brief Summary of full Prescribing Information on the following page. To learn more, visit Pharmacyclics, Inc. 215 Janssen Biotech, Inc /15 PRC-77

9 Brief Summary of Prescribing Information for IMBRUVICA (ibrutinib) IMBRUVICA (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verifcation of clinical beneft in confrmatory trials [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the beneft-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fbrillation and atrial futter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fbrillation. Periodically monitor patients clinically for atrial fbrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fbrillation persists, consider the risks and benefts of IMBRUVICA treatment and dose modifcation [see Dosage and Administration (2.3) in Full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity: Based on fndings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 2 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 56 mg per day and 42 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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 hazard to a fetus [see Use in Specifc Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage [see Warnings and Precautions] Infections [see Warnings and Precautions] Cytopenias [see Warnings and Precautions] Atrial Fibrillation [see Warnings and Precautions] Second Primary Malignancies [see Warnings and Precautions] Tumor Lysis Syndrome [see Warnings and Precautions] IMBRUVICA (ibrutinib) capsules Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not refect the rates observed in practice. Clinical Trials Experience: Mantle Cell Lymphoma: The data described below refect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 56 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions ( 2%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions ( 5%) were pneumonia, abdominal pain, atrial fbrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 56 mg daily occurring at a rate of 1% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in 1% of Patients with MCL (N=111) System Organ Class Gastrointestinal Infections and infestations General and administrative site conditions Skin and subcutaneous tissue Musculoskeletal and connective tissue Respiratory, thoracic and mediastinal Metabolism and nutrition Nervous system Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache All Grades Grade 3 or 4 Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 Platelets Decreased Neutrophils Decreased Hemoglobin Decreased 41 9 * Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

10 IMBRUVICA (ibrutinib) capsules Patients with MCL who develop lymphocytosis greater than 4,/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 1 mg/dl. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below refect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 ( 2%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculo skeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately fve percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 42 mg daily occurring at a rate of 1% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in 1% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal Infections and infestations General and administrative site conditions Skin and subcutaneous tissue Respiratory, thoracic and mediastinal Musculoskeletal and connective tissue Nervous system Metabolism and nutrition Neoplasms benign, malignant, unspecifed Injury, poisoning and procedural complications Psychiatric Preferred Term Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy All Grades Grade 3 or 4 Decreased appetite 17 2 Second malignancies* 1* Laceration 1 2 Anxiety Insomnia 1 1 Vascular Hypertension 17 8 *One patient death due to histiocytic sarcoma IMBRUVICA (ibrutinib) capsules Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 Platelets Decreased 71 1 Neutrophils Decreased Hemoglobin Decreased 44 * Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 refect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions 1% Reported in Study 2 System Organ Class ADR Term All Grades IMBRUVICA (N=195) Grade 3 or 4 Ofatumumab (N=191) All Grades Grade 3 or 4 Gastrointestinal Diarrhea Nausea Stomatitis* Constipation 15 9 Vomiting General and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue Rash* Petechiae 14 1 Bruising* 12 1 Musculoskeletal and connective tissue Musculoskeletal Pain* Arthralgia Nervous system Headache Dizziness 11 5 Injury, poisoning and procedural complications Contusion 11 3 Eye Vision blurred 1 3 Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms

11 IMBRUVICA (ibrutinib) capsules Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2 All Grades IMBRUVICA (N=195) Grade 3 or 4 Ofatumumab (N=191) All Grades Grade 3 or 4 Neutrophils Decreased Platelets Decreased Hemoglobin Decreased * Based on laboratory measurements per IWCLL criteria Waldenström s Macroglobulinemia The data described below refect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial ( 2%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 refect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in 1% of Patients with Waldenström s Macroglobulinemia (N=63) System Organ Class Gastrointestinal Skin and subcutaneous tissue General and administrative site conditions Musculoskeletal and connective tissue Infections and infestations Respiratory, thoracic and mediastinal Nervous system Neoplasms benign, malignant, and unspecifed (including cysts and polyps) Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal refux disease Rash* Bruising* Pruritus All Grades Grade 3 or 4 Fatigue 21 Muscle spasms Arthropathy Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough Dizziness Headache Skin cancer* 11 The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63) Percent of Patients (N=63) 6 2 All Grades Grade 3 or 4 Platelets Decreased Neutrophils Decreased Hemoglobin Decreased 13 8 * Based on laboratory measurements. IMBRUVICA (ibrutinib) capsules Postmarketing Experience: The following adverse reactions have been identifed during post-approval use of IMBRUVICA. 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. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P45 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased C max and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of mg) given for 28 days with single dose AUC values of 1445 ± 869 ng hr/ml which is approximately 5% greater than steady state exposures seen at the highest indicated dose (56 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib C max and AUC by approximately 13- and 1-fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on fndings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 1, 4 and 8 mg/kg/day. Ibrutinib at a dose of 8 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 8 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 2 times the exposure in patients with CLL or WM administered the dose of 56 mg daily and 42 mg daily, respectively. Ibrutinib at doses of 4 mg/kg/day or greater was associated with decreased fetal weights. The dose of 4 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 56 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fbrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information]. Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fbrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 ml/min. There are no data in patients with severe renal impairment (CLcr < 25 ml/min) or patients on dialysis [see Clinical Pharmacology (12.3) in Full Prescribing Information].

12 IMBRUVICA (ibrutinib) capsules Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modifcation guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specifc Populations]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifcations to IMBRUVICA dosing are not required. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions]. Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions]. Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. Inform patients to take IMBRUVICA orally once daily according to their physician s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information]. Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in Full Prescribing Information]. Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 9485 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 1944 Patent IMBRUVICA is a registered trademark owned by Pharmacyclics, Inc. Pharmacyclics, Inc. 215 Janssen Biotech, Inc. 215 PRC-786 Join the Conversation Share content and connect online with ASH and your colleagues around the globe Follow us on Twitter Like us on Facebook at AmericanSocietyofHematology Get real-time updates and share your opinion on: l Breaking hematology and oncology news l Updates on ASH meetings and activities l ASH media alerts and press releases l Updates about the Society s advocacy efforts l ASH award and grant opportunities l Society newsletters and publications

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15 NOW AVAILABLE FOR THE TREATMENT OF Ph-NEGATIVE RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Discover the first and only FDA-approved Bispecific CD19-directed CD3 T-cell Engager In a phase 2, open-label, multicenter, single-arm clinical trial: The primary endpoint was the complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eligible patients were 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-precursor ALL. Relapsed or refractory was defined as relapsed with first remission duration of 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had 1% blasts in bone marrow. 41.6% (95% CI: ) of R/R ALL evaluable patients achieved a CR/CRh* (n=77/185) % (95% CI: ) with CR/CRh* also had an MRD response (defned as MRD by PCR < 1 x 1-4 ) (n=58/77) 1 39% of patients who achieved CR/CRh* went on to receive allogeneic transplant (n=3/77) 1 INDICATION BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. IMPORTANT SAFETY INFORMATION WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Contraindications BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation. Warnings and Precautions Cytokine Release Syndrome (CRS): Life-threatening or fatal CRS occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI) _R2_AMG_AAUS_JrnlAd_Blood_Sprd.indd 1-2

16 Neurological Toxicities: Approximately 5% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech, disturbances in consciousness, confusion and disorientation, and coordination and balance. The median time to onset of any neurological toxicity was 7 days. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI. Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed. Tumor Lysis Syndrome (TLS): Life-threatening or fatal TLS has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events. Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs. Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Elevated Liver Enzymes: Transient elevations in liver enzymes are associated with BLINCYTO treatment. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN. Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy. Preparation and administration errors have occurred. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose). Adverse Events The most commonly reported adverse reactions ( 2%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (2%) and constipation (2%). Dosage and Administration Guidelines BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose). Please see accompanying Brief Summary of Prescribing Information on adjacent pages. R/R=relapsed/refractory; CR=complete remission; CRh*=complete remission with partial hematological recovery; MRD=minimal residual disease Discover the first and only FDA-approved Bispecific CD19-directed CD3 T-cell Engager VISIT BLINCYTO.COM TO LEARN MORE Reference: 1. BLINCYTO (blinatumomab) Prescribing Information, Amgen. BLINCYTO is a trademark of Amgen Inc. 215 Amgen Inc. All rights reserved. USA /15 2/5/15 1:58 PM

17 Summary of Prescribing Information BLINCYTO (blinatumomab) for injection, for intravenous use WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), which may be lifethreatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Neurological toxicities, which may be severe, lifethreatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.2)]. 1. INDICATIONS AND USAGE BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials [see Clinical Studies (14.1)]. 4. CONTRAINDICATIONS BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. 5. WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome Cytokine Release Syndrome (CRS), which may be lifethreatening or fatal, occurred in patients receiving BLINCYTO. Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS. Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was infrequently reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS. Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.2 Neurological Toxicities In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 5% of patients. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, lifethreatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 15% of patients and included encephalopathy, convulsions, speech, disturbances in consciousness, confusion and disorientation, and coordination and balance. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.3)]. 5.3 Infections In patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and ontreatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.5 Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including lifethreatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. 5.6 Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. 5.7 Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. In patients receiving BLINCYTO in clinical trials, Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal. 5.8 Leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 5.9 Preparation and Administration Errors Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.2) and (2.4)]. 6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cytokine Release Syndrome [see Warnings and Precautions (5.1)] Neurological Toxicities [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Neutropenia and Febrile Neutropenia [see Warnings and Precautions (5.5)] Effects on Ability to Drive and Use Machines [see Warnings and Precautions (5.6)] Elevated Liver Enzymes [see Warnings and Precautions (5.7)] Leukoencephalopathy [see Warnings and Precautions (5.8)] Preparation and Administration Errors [see Warnings and Precautions (5.9)] 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. The safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American. The most common adverse reactions ( 2%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (2%). Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions ( 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache. Adverse reactions of Grade 3 or higher were reported in 8% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission. The adverse reactions with 1% incidence for any grade or 5% incidence for Grade 3 or higher are summarized in Table 2. Table 2. Adverse Reactions With 1% Incidence for Any Grade or 5% Incidence for Grade 3 or higher (N = 212) Adverse Reaction Any Grade 1 Blood and lymphatic system Febrile neutropenia Anemia Neutropenia Thrombocytopenia 11 8 Leukopenia 9 8 Gastrointestinal Nausea 25 Constipation 2 < 1 Diarrhea Abdominal pain 15 2 Vomiting 13 General and administration site conditions Pyrexia 62 7 Peripheral edema 25 < 1 Fatigue 17 1 Chills 15 Chest pain 11 1 Grade 3 or higher _R2_AMG_AAUS_JrnlAd_Blood_Sprd.indd 3-4

18 Table 2 (continued) Immune system Cytokine release syndrome Infections and infestations Other pathogen infections Bacterial infections Fungal infections 15 7 Viral infections 13 4 Pneumonia 9 8 Sepsis 7 6 Investigations Increased alanine aminotransferase Increased aspartate aminotransferase Increased weight 11 Metabolism and nutrition Hypokalemia 23 6 Hypomagnesemia 12 Hyperglycemia 11 7 Decreased appetite 1 3 Hypophosphatemia 6 5 Musculoskeletal and connective tissue Back pain 14 2 Pain in extremity 12 1 Bone pain 11 3 Arthralgia 1 2 Nervous system Headache 36 3 Tremor Dizziness 14 < 1 Psychiatric Insomnia 15 Respiratory, thoracic, and mediastinal Cough 19 Dyspnea Skin and subcutaneous tissue Rash Vascular Hypotension 11 2 Hypertension Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version Diarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis. 3 Tremor includes the following terms: resting tremor and tremor. 4 Dyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing. 5 Rash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and vesicular rash. Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were: Blood and lymphatic system : leukocytosis (2%), lymphopenia (1%), Cardiac : tachycardia (8%), General and administration site conditions: edema (5%), Immune system : cytokine storm (1%), Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gammaglutamyl-transferase (6%), increased liver enzymes (1%), Metabolism and nutrition : tumor lysis syndrome (4%), hypoalbuminemia (4%), Nervous system : encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder (< 1%), Psychiatric : confusion (7%), disorientation (3%), Vascular : capillary leak syndrome (< 1%). Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%). 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In clinical studies, less than 1% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing antiblinatumomab antibodies. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events. If formation of anti-blinatumomab antibodies with a clinically signifcant effect is suspected, contact Amgen at AMGEN ( ) to discuss antibody testing. The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specifcity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be infuenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading. 7. DRUG INTERACTIONS No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP45 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP45 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2 and 12.3)]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BLINCYTO in pregnant women. Based on its mechanism of action, BLINCYTO may cause fetal toxicity including B-cell lymphocytopenia when administered to a pregnant woman. BLINCYTO should be used during pregnancy only if the potential beneft justifes the potential risk to the fetus. Animal Data Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryofetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses. 8.3 Lactation It is not known whether blinatumomab is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from blinatumomab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use There is limited experience in pediatric patients. BLINCYTO was evaluated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL. The median age was 6 years (range: 2 to 17 years). BLINCYTO was administered at doses of 5 to 3 mcg/m 2 /day. The recommended phase 2 regimen was 5 mcg/m 2 /day on Days 1-7 and 15 mcg/m 2 /day on Days 8-28 for cycle 1, and 15 mcg/m 2 /day on Days 1-28 for subsequent cycles. At a higher dose, a fatal cardiac failure event occurred in the setting of life-threatening cytokine release syndrome (CRS) [see Warnings and Precautions (5.1)]. The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens. 8.5 Geriatric Use Of the total number of patients with relapsed or refractory ALL, approximately 13% were 65 years of age and over. Generally, safety and effcacy were similar between elderly patients ( 65 years of age) and patients less than 65 years of age treated with BLINCYTO. Elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections [see Warnings and Precautions (5.2) and (5.3)]. 8.6 Hepatic Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with hepatic impairment. 8.7 Renal Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with renal impairment. No dose adjustment is needed for patients with baseline creatinine clearance (CrCL) equal to or greater than 3 ml/min. There is no information available in patients with CrCL less than 3 ml/min or patients on hemodialysis [see Clinical Pharmacology (12.3)]. 1. OVERDOSAGE Overdoses have been observed, including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care [see Warnings and Precautions (5.9)]. Consider reinitiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion [see Dosage and Administration (2.1)]. This brief summary using 12/3/214 FDA Approved label. BLINCYTO (blinatumomab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA USA Patent: 215 Amgen Inc. All rights reserved. 1/15 2/5/15 2: PM

19 ISTODAX (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. ISTODAX FOR THE 2ND-LINE TREATMENT OF PTCL Study Design Efcacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131) in a pretreated, histologically diverse PTCL population. All patients received prior systemic therapy for PTCL. Patients could be treated until disease progression at their discretion and that of the investigator. Important Safety Information WARNINGS AND PRECAUTIONS Myelosuppression: ISTODAX (romidepsin) can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 3 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISTODAX Tumor lysis syndrome: TLS (Tumor lysis syndrome) has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (2%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). ISTODAX is a registered trademark of Celgene Corporation. 214 Celgene Corporation 11/14 US-IST145

20 UPDATED STUDY 3 DATA 6% (12/2) of complete responses were known to exceed Months Follow-up on the remaining 8 patients was discontinued prior to 8.5 months 1 8 Months % ORR (34/13) 1 (CR + CRu + PR) [95% CI: 18.8, 34.6] 15% CR/CRu (CR + CRu) [95% CI: 9.7, 22.8] (2/13) 1 Primary Endpoint 56 days (1.8 months, n=34) median time to objective disease response 2 Two sided 95% confidence interval. Response rates above are rounded to the nearest whole number. CR=complete response; CRu=complete response unconfirmed; ORR=objective disease response; PR=partial response. Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 26 patients (2%) experienced a serious infection, including 6 patients (5%) with serious treatmentrelated infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (4%), constipation (4%), and diarrhea (36%). DRUG INTERACTIONS Monitor more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives Romidepsin is metabolized by CYP3A4 Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4 Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors USE IN SPECIFIC POPULATIONS Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information on the following pages. References: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; Data on file, Celgene Corporation, Summit, NJ. 1-MG SINGLE-USE VIAL