b'Brief Summary of Prescribing Information for IMBRUVICA (ibrutinib) IMBRUVICA (ibrutinib) IMBRUVICA (ibrutinib) capsules, for oral useIMBRUVICA (ibrutinib) tablets, for oral use Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported INDICATIONS AND USAGE with IMBRUVICA. Assess the baseline risk (e.g., high tumor burden) and take Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: IMBRUVICAappropriate precautions. Monitor patients closely and treat as appropriate. is indicated for the treatment of adult patients with chronic lymphocyticEmbryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause leukemia (CLL)/small lymphocytic lymphoma (SLL). fetal harm when administered to a pregnant woman. Administration of ibrutinib Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17ptopregnantratsandrabbitsduringtheperiodoforganogenesiscaused embryo-fetal toxicity including malformations at exposures that were 2-20 times deletion: IMBRUVICA is indicated for the treatment of adult patients withhigher than those reported in patients with hematologic malignancies. Advise chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) withpregnant women of the potential risk to a fetus. Advise females of reproductive 17p deletion. potential to use effective contraception during treatment with IMBRUVICA and CONTRAINDICATIONS for 1 month after the last dose. [see Use in Specific Populations].None ADVERSE REACTIONSWARNINGS AND PRECAUTIONS The following clinically significant adverse reactions are discussed in more Hemorrhage: Fatal bleeding events have occurred in patients who receiveddetail in other sections of the labeling:IMBRUVICA. Major hemorrhage ( Grade 3, serious, or any central nervousHemorrhage [see Warnings and Precautions]system events; e.g., intracranial hemorrhage [including subdural hematoma],Infections [see Warnings and Precautions]gastrointestinalbleeding,hematuria,andpostproceduralhemorrhage)Cytopenias [see Warnings and Precautions]occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patientsCardiac Arrhythmias [see Warnings and Precautions]who received IMBRUVICA in 27 clinical trials. Bleeding events, includingHypertension [see Warnings and Precautions]bruising and petechiae, occurred in 39% of patients who received IMBRUVICA.The mechanism for the bleeding events is not well understood.Second Primary Malignancies [see Warnings and Precautions]Use of either anticoagulant or antiplatelet agents concomitantly withTumor Lysis Syndrome [see Warnings and Precautions]IMBRUVICA increases the risk of major hemorrhage. Across clinical trials,Clinical Trials Experience: Because clinical trials are conducted under 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet orwidely variable conditions, adverse event rates observed in clinical trials anticoagulant therapy experienced major hemorrhage. The addition ofof a drug cannot be directly compared with rates of clinical trials of another antiplatelet therapy with or without anticoagulant therapy increased thisdrug and may not reflect the rates observed in practice.percentage to 4.4%, and the addition of anticoagulant therapy with or withoutThe data in the WARNINGS AND PRECAUTIONS reflect exposure to IMBRUVICA antiplatelet therapy increased this percentage to 6.1%. Consider the risks andin 6 trials as a single agent at 420 mg orally once daily in 475 patients and at 560 mgbenefits of anticoagulant or antiplatelet therapy when co-administered withorally once daily in 174 patients and in 4 trials administered in combination IMBRUVICA. Monitor for signs and symptoms of bleeding. with other drugs at 420 mg orally once daily in 827 patients. Among these Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days1,476 patients with B-cell malignancies who received IMBRUVICA, 87% were pre- and post-surgery depending upon the type of surgery and the risk ofexposed for 6 months or longer and 68% were exposed for greater than one bleeding [see Clinical Studies (14) in Full Prescribing Information]. year.In this pooled safety population of 1,476 patients with B-cell malignancies, Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal)the most common adverse reactions (30%) were thrombocytopenia, diarrhea, haveoccurredwithIMBRUVICAtherapy.Grade3orgreaterinfectionsfatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.occurred in 21% of 1,476 patients who received IMBRUVICA in clinical trials [seeChronicLymphocyticLeukemia/SmallLymphocyticLymphoma:Thedata Adverse Reactions]. Cases of progressive multifocal leukoencephalopathydescribed below reflect exposure to IMBRUVICA in one single-arm, open-(PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patientslabel clinical trial (Study 1102) and five randomized controlled clinical trials treated with IMBRUVICA. Consider prophylaxis according to standard of care(RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with in patients who are at increased risk for opportunistic infections. Monitor andCLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA). In evaluate patients for fever and infections and treat appropriately. general, patients with creatinine clearance (CLcr)30 mL/min, AST or ALT Cytopenias:In645patientswithB-cellmalignancieswhoreceived 2.5 x ULN, or total bilirubin1.5x ULN (unless of non-hepatic origin) were IMBRUVICA as a single agent, grade 3 or 4 neutropenia occurred in 23% ofexcluded from these trials. In Study E1912, patients with AST or ALT 3 x ULN patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 3%,or total bilirubin 2.5 x ULN were excluded. Study 1102 included 51 patients based on laboratory measurements. with previously treated CLL/SLL. RESONATE included 386 randomized patients Monitor complete blood counts monthly.with previously treated CLL or SLL who received single agent IMBRUVICA or Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurredofatumumab. RESONATE-2 included 267 randomized patients with treatment with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurrednave CLL or SLL who were 65 years or older and received single agent in 0.2% of patients and Grade 3 or greater atrial fibrillation and atrial flutterIMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with occurredin4%of1,476patientswhoreceivedIMBRUVICAinclinicalpreviously treated CLL or SLL who received IMBRUVICA in combination with trials. These events have occurred particularly in patients with cardiac riskBR or placebo in combination with BR. iLLUMINATE included 228 randomized factors, hypertension, acute infections, and a previous history of cardiacpatients with treatment nave CLL/SLL who were 65 years or older or with arrhythmias. [see Adverse Reactions]. coexistingmedicalconditionsandreceivedIMBRUVICAincombination Periodically monitor patients clinically for cardiac arrhythmias. Obtain anwithobinutuzumaborchlorambucilincombinationwithobinutuzumab. ECG for patients who develop arrhythmic symptoms (e.g., palpitations,E1912 included 510 patients with previously untreated CLL/SLL who were lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac70 years or younger and received IMBRUVICA in combination with rituximab arrhythmias appropriately, and if it persists, consider the risks and benefits ofor received fludarabine, cyclophosphamide, and rituximab (FCR). IMBRUVICA treatment and follow dose modification guidelines [see Dosage The most common adverse reactions in patients with CLL/SLL receiving and Administration (2.2) in Full Prescribing Information].IMBRUVICA(30%)werethrombocytopenia,diarrhea,fatigue, Hypertension: Hypertension occurred in 19% of 1,476 patients who receivedmusculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred inFour to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued 8% of patients. Based on data from 1,124 of these patients, the median timetreatment due to adverse reactions. These included pneumonia, hemorrhage, to onset was 5.9 months (range, 0.03 to 24 months). atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. Adverse Monitor blood pressure in patients treated with IMBRUVICA and initiate orreactions leading to dose reduction occurred in approximately 9% of patients.adjust anti-hypertensive medication throughout treatment with IMBRUVICAStudy 1102 : Adverse reactions and laboratory abnormalities from Study 1102 as appropriate. (N=51) using single agent IMBRUVICA 420mg daily in patients with previously Second Primary Malignancies: Other malignancies (10%), including non- treated CLL/SLL occurring at a rate of10% with a median duration of skin carcinomas (4%), occurred among the 1,476 patients who receivedtreatment of 15.6 months are presented in Tables 1 and2.IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).'