Ibrutinib

CLL/SLL and WM : 420 mg taken orally once daily ( 2.1 ). cGVHD :

• Patients 12 years and older: 420 mg taken orally once daily ( 2.1 ).
• Patients 1 to less than 12 years of age: 240 mg/m 2 taken orally once daily (up to a dose of 420 mg) ( 2.1 ). Tablets or capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. See full prescribing information for oral suspension administration instructions ( 2.1 ).

2.1 Recommended Dosage Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s Macroglobulinemia The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily until disease progression or unacceptable toxicity. For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR). For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab. When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day. Chronic Graft versus Host Disease The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is 420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240 mg/m 2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical assessment of the individual patient. Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than 12 years of age using either IMBRUVICA capsules/tablets or oral suspension Recommended dose to achieve 240 mg/m 2 BSA* (m 2 ) Range Dose (mg) of IMBRUVICA Capsules/Tablets to Administer Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer > 0.3 to 0.4 - 1.2 mL > 0.4 to 0.5 - 1.5 mL > 0.5 to 0.6 - 1.9 mL > 0.6 to 0.7 - 2.2 mL > 0.7 to 0.8 210 mg 2.6 mL > 0.8 to 0.9 210 mg 2.9 mL > 0.9 to 1 210 mg 3.3 mL > 1 to 1.1 280 mg 3.6 mL > 1.1 to 1.2 280 mg 4 mL > 1.2 to 1.3 280 mg 4.3 mL > 1.3 to 1.4 350 mg 4.6 mL > 1.4 to 1.5 350 mg 5 mL > 1.5 to 1.6 350 mg 5.3 mL > 1.6 420 mg 6 mL *BSA = body surface area. Administration Administer IMBRUVICA at approximately the same time each day. Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. Follow Instructions for Use for further administration details of IMBRUVICA oral suspension. If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Do not take extra doses of IMBRUVICA to make up for the missed dose.

2.2 Dosage Modifications for Adverse Reactions For adverse reactions listed in Table 2 , interrupt IMBRUVICA therapy. Once the adverse reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage modifications (see Table 2 ). Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction a,b Occurrence Dose Modification for CLL/SLL, WM, and Patients 12 Years or older with cGVHD After Recovery Starting Dose = 420 mg Dose Modification for Patients 1 Year to less than 12 Years with cGVHD After Recovery Starting Dose = 240 mg/m 2 Grade 2 cardiac failure First Restart at 280 mg daily c Restart at 160 mg/m 2 daily c Second Restart at 140 mg daily c Restart at 80 mg/m 2 daily c Third Discontinue IMBRUVICA Discontinue IMBRUVICA Grade 3 cardiac arrhythmias First Restart at 280 mg daily c Restart at 160 mg/m 2 daily c Second Discontinue IMBRUVICA Discontinue IMBRUVICA Grade 3 or 4 cardiac failure Grade 4 cardiac arrhythmias First Discontinue IMBRUVICA Discontinue IMBRUVICA Other Grade 3 or 4 non-hematological toxicities d Grade 3 or 4 neutropenia with infection or fever Grade 4 hematological toxicities First Restart at 280 mg daily Restart at 160 mg/m 2 daily c Second Restart at 140 mg daily Restart at 80 mg/m 2 daily c Third Discontinue IMBRUVICA Discontinue IMBRUVICA a [see Warnings and Precautions ( 5 ) ] . b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL. c Evaluate the benefit-risk before resuming treatment. d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment. Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA capsules/tablets or oral suspension Recommended dose to achieve 160 mg/m 2 Recommended dose to achieve 80 mg/m 2 BSA* (m 2 ) Range Dose (mg) of IMBRUVICA Capsules/Tablets to Administer Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer Dose (mg) of IMBRUVICA Capsules/Tablets to Administer Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer > 0.3 to 0.4 - 0.8 mL - 0.4 mL > 0.4 to 0.5 - 1 mL - 0.5 mL > 0.5 to 0.6 - 1.3 mL - 0.6 mL > 0.6 to 0.7 - 1.5 mL - 0.7 mL > 0.7 to 0.8 140 mg 1.7 mL 70 mg 0.9 mL > 0.8 to 0.9 140 mg 1.9 mL 70 mg 1 mL > 0.9 to 1 140 mg 2.2 mL 70 mg 1.1 mL > 1 to 1.1 140 mg 2.4 mL 70 mg 1.2 mL > 1.1 to 1.2 210 mg 2.6 mL - 1.3 mL > 1.2 to 1.3 210 mg 2.9 mL - 1.4 mL > 1.3 to 1.4 210 mg 3.1 mL - 1.5 mL > 1.4 to 1.5 210 mg 3.3 mL 140 mg 1.7 mL > 1.5 to 1.6 280 mg 3.5 mL 140 mg 1.8 mL > 1.6 280 mg 4 mL 140 mg 2 mL *BSA = body surface area.

2.3 Dosage Modifications for Use with CYP3A Inhibitors Recommended dosage modifications are described below [see Drug Interactions ( 7.1 )] : Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors Patient Population Coadministered Drug Recommended IMBRUVICA Dosage B-cell Malignancies Moderate CYP3A inhibitor 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 140 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 70 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2 )]. Other strong CYP3A inhibitors Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. Patients 12 years and older with cGVHD Moderate CYP3A inhibitor 420 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 140 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2 )]. Other strong CYP3A inhibitors Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. Patients 1 year to less than 12 years of age with cGVHD Moderate CYP3A inhibitors 240 mg/m 2 once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. Voriconazole for suspension 9 mg/kg (maximum dose: 350 mg) twice daily 160 mg/m 2 once daily Posaconazole at any dosage 80 mg/m 2 once daily Other strong CYP3A inhibitors Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 )] .

2.4 Dosage Modifications for Use in Hepatic Impairment Adult Patients with B-cell Malignancies The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A). The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-Pugh class B). Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. Patients with cGVHD The recommended dosage is 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). The recommended dosage is 80 mg/m 2 daily for patients 1 to less than 12 years of age with total bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome). Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] .

5 WARNINGS AND PRECAUTIONS Hemorrhage : Monitor for bleeding and manage ( 5.1 ). Infections : Monitor patients for fever and infections, evaluate promptly, and treat ( 5.2 ). Cardiac Arrhythmias , Cardiac Failure , and Sudden Death : Monitor for symptoms of arrhythmias and cardiac failure and manage ( 5.3 ). Hypertension : Monitor blood pressure and treat ( 5.4 ). Cytopenias : Check complete blood counts monthly ( 5.5 ). Second Primary Malignancies : Other malignancies have occurred in patients, including skin cancers, and other carcinomas ( 5.6 ). Hepatotoxicity, Including Drug- Induced Liver Injury : Monitor hepatic function throughout treatment ( 5.7 ). Tumor Lysis Syndrome (TLS) : Assess baseline risk and take precautions. Monitor and treat for TLS ( 5.8 ). Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.9 , 8.1 , 8.3 ).

5.1 Hemorrhage Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA, respectively [see Adverse Reactions ( 6.1 )] . The mechanism for the bleeding events is not well understood. Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding. Consider the benefit-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 )].

5.2 Infections Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions ( 6.1 , 6.2 )] . Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.

5.3 Cardiac Arrhythmias, Cardiac Failure, and Sudden Death Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events. Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections [see Adverse Reactions ( 6.1 )] . Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines [see Dosage and Administration ( 2.2 )] , and consider the risks and benefits of continued IMBRUVICA treatment.

5.4 Hypertension Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see Adverse Reactions ( 6.1 )] . Based on data from a subset of these patients (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98 months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%. Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration ( 2.2 )] .

5.5 Cytopenias In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions ( 6.1 )] . Monitor complete blood counts monthly.

5.6 Second Primary Malignancies Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions ( 6.1 )] . The most frequent second primary malignancy was non-melanoma skin cancer (6%).

5.7 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including IMBRUVICA. Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA. For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA. 5. 8 Tumor Lysis Syndrome Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse Reactions ( 6.2 )] . Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate. 5. 9 Embryo-Fetal Toxicity Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 3-20 times higher than those reported in patients with hematologic malignancies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose. [see Use in Specific Populations ( 8.1 )] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Cytopenias [see Warnings and Precautions ( 5.5 )] Second Primary Malignancies [see Warnings and Precautions ( 5.6 )] Hepatotoxicity, including DILI [see Warning s and Precautions ( 5.7 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.8 )] The most common (≥30%) adverse reactions in patients with B-cell malignancies are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea ( 6 ). The most common (≥20%) adverse reactions in adult or pediatric patients with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia, musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage, nausea, abdominal pain, pneumonia, and headache ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma The data described below reflect exposure to IMBRUVICA in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab. RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR). The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 9% of patients. Study 1102 Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Table 5 and Table 6 . Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102 Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%) Gastrointestinal disorders Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia 59 22 20 20 18 14 12 4 2 2 0 2 0 0 Skin and subcutaneous tissue disorders Bruising Rash Petechiae 51 25 16 2 0 0 Infections and infestations Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection 47 22 16 12 12 2 6 6 10 2 General disorders and administration site conditions Fatigue Pyrexia Peripheral edema Asthenia Chills 33 24 22 14 12 6 2 0 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Arthralgia Muscle spasms 25 24 18 6 0 2 Respiratory, thoracic and mediastinal disorders Cough Oropharyngeal pain Dyspnea 22 14 12 0 0 0 Nervous system disorders Dizziness Headache 20 18 0 2 Vascular disorders Hypertension 16 8 Metabolism and nutrition disorders Decreased appetite 16 2 Neoplasms benign, malignant, unspecified Second malignancies 10 2 † † One patient death due to histiocytic sarcoma. Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102 Percent of Patients (N=51) All Grades (%) Grade 3 or 4 (%) Platelets decreased 69 12 Neutrophils decreased 53 26 Hemoglobin decreased 43 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions. Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients. RESONATE Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL. Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE Body System Adverse Reaction IMBRUVICA (N=195) Ofatumumab (N=191) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) Gastrointestinal disorders Diarrhea 48 4 18 2 Nausea 26 2 18 0 Stomatitis* 17 1 6 1 Constipation 15 0 9 0 Vomiting 14 0 6 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 28 2 18 1 Arthralgia 17 1 7 0 Muscle spasms 13 0 8 0 Skin and subcutaneous tissue disorders Rash* 24 3 13 0 Petechiae 14 0 1 0 Bruising* 12 0 1 0 General disorders and administration site conditions Pyrexia 24 2 15 2 † Respiratory, thoracic and mediastinal disorders Cough 19 0 23 1 Dyspnea 12 2 10 1 Infections and infestations Upper respiratory tract infection 16 1 11 2 † Pneumonia* 15 12 † 13 10 † Sinusitis* 11 1 6 0 Urinary tract infection 10 4 5 1 Nervous system disorders Headache 14 1 6 0 Dizziness 11 0 5 0 Injury, poisoning and procedural complications Contusion 11 0 3 0 Eye disorders Vision blurred 10 0 3 0 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms. † Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a fatal outcome in the ofatumumab arm. Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE IMBRUVICA (N=195) Ofatumumab (N=191) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Neutrophils decreased 51 23 57 26 Platelets decreased 52 5 45 10 Hemoglobin decreased 36 0 21 0 Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia (8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients. RESONATE-2 Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2. Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2 Body System Adverse Reaction IMBRUVICA (N=135) Chlorambucil (N=132) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) Gastrointestinal disorders Diarrhea 42 4 17 0 Nausea 22 1 39 1 Constipation 16 1 16 0 Stomatitis* 14 1 4 1 Vomiting 13 0 20 1 Abdominal pain 13 3 11 1 Dyspepsia 11 0 2 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 36 4 20 0 Arthralgia 16 1 7 1 Muscle spasms 11 0 5 0 General disorders and administration site conditions Fatigue 30 1 38 5 Peripheral edema 19 1 9 0 Pyrexia 17 0 14 2 Respiratory, thoracic and mediastinal disorders Cough 22 0 15 0 Dyspnea 10 1 10 0 Skin and subcutaneous tissue disorders Rash* 21 4 12 2 Bruising* 19 0 7 0 Eye disorders Dry eye 17 0 5 0 Lacrimation increased 13 0 6 0 Vision blurred 13 0 8 0 Visual acuity reduced 11 0 2 0 Infections and infestations Upper respiratory tract infection 17 2 17 2 Skin infection* 15 2 3 1 Pneumonia* 14 8 7 4 Urinary tract infections 10 1 8 1 Vascular disorders Hypertension* 14 4 1 0 Nervous system disorders Headache 12 1 10 2 Dizziness 11 0 12 1 Investigations Weight decreased 10 0 12 0 Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms. Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE-2 IMBRUVICA (N=135) Chlorambucil (N=132) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Neutrophils Decreased 55 28 67 31 Platelets Decreased 47 7 58 14 Hemoglobin Decreased 36 0 39 2 Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia (11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients. HELIOS Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL. Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS Body System Adverse Reaction IMBRUVICA + BR (N=287) Placebo + BR (N=287) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) Blood and lymphatic system disorders Neutropenia* 66 61 60 56 † Thrombocytopenia* 34 16 26 16 Gastrointestinal disorders Diarrhea 36 2 23 1 Abdominal pain 12 1 8 <1 Skin and subcutaneous tissue disorders Rash* 32 4 25 1 Bruising * 20 <1 8 <1 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 29 2 20 0 Muscle spasms 12 <1 5 0 General disorders and administration site conditions Pyrexia 25 4 22 2 Vascular disorders Hemorrhage* 19 2 † 9 1 Hypertension* 11 5 5 2 Infections and infestations Bronchitis 13 2 10 3 Skin infection* 10 3 6 2 Metabolism and nutrition disorders Hyperuricemia 10 2 6 0 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms. <1 used for frequency above 0 and below 0.5%. † Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in the placebo + BR arm. Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR. iLLUMINATE Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL. Table 12: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE Body System Adverse Reaction IMBRUVICA + Obinutuzumab (N=113) Chlorambucil + Obinutuzumab (N=115) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) Blood and lymphatic system disorders Neutropenia* 48 39 64 48 Thrombocytopenia* 36 19 28 11 Anemia 17 4 25 8 Skin and subcutaneous tissue disorders Rash* 36 3 11 0 Bruising* 32 3 3 0 Gastrointestinal disorders Diarrhea 34 3 10 0 Constipation 16 0 12 1 Nausea 12 0 30 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 33 1 23 3 Arthralgia 22 1 10 0 Muscle spasms 13 0 6 0 Respiratory, thoracic and mediastinal disorders Cough 27 1 12 0 Injury, poisoning and procedural complications Infusion related reaction 25 2 58 8 Vascular disorders Hemorrhage* 25 1 9 0 Hypertension* 17 4 4 3 General disorders and administration site conditions Pyrexia 19 2 26 1 Fatigue 18 0 17 2 Peripheral edema 12 0 7 0 Infections and infestations Pneumonia* 16 9 9 4 † Upper respiratory tract infection 14 1 6 0 Skin infection* 13 1 3 0 Urinary tract infection 12 3 7 1 Nasopharyngitis 12 0 3 0 Conjunctivitis 11 0 2 0 Metabolism and nutrition disorders Hyperuricemia 13 1 0 0 Cardiac disorders Atrial fibrillation 12 5 0 0 Psychiatric disorders Insomnia 12 0 4 0 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms. † Includes one event with a fatal outcome. E1912 Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger. Table 13: Adverse Reactions Reported in ≥ 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912 Body System Adverse Reaction IMBRUVICA + Rituximab (N=352) Fludarabine + Cyclophosphamide + Rituximab (N=158) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) General disorders and administration site conditions Fatigue 80 2 78 3 Peripheral edema 28 1 17 0 Pyrexia 27 1 27 1 Pain 23 2 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 61 5 35 2 Arthralgia 41 5 10 1 Gastrointestinal disorders Diarrhea 53 4 27 1 Nausea 40 1 64 1 Stomatitis* 22 1 8 1 Abdominal pain* 19 2 10 1 Vomiting 18 2 28 0 Constipation 17 0 32 0 Skin and subcutaneous tissue disorders Rash* 49 4 29 5 Bruising* 36 1 4 1 Vascular disorders Hypertension* 42 19 22 6 Hemorrhage* 31 2 8 1 Nervous system disorders Headache 40 1 27 1 Dizziness 21 1 13 1 Peripheral neuropathy* 19 1 13 1 Respiratory, thoracic and mediastinal disorders Cough 32 0 25 0 Dyspnea 22 2 21 1 Infections and infestations Upper respiratory tract 29 1 19 2 infection Skin infection* 16 1 3 1 Metabolism and nutrition disorders Hyperuricemia 19 1 4 0 Decreased appetite 15 0 20 1 Psychiatric disorders Insomnia 16 1 19 1 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms. Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving IMBRUVICA (E1912) IMBRUVICA + Rituximab (N=352) Fludarabine + Cyclophosphamide + Rituximab (N=158) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology abnormalities Neutrophils decreased Platelets decreased Hemoglobin decreased 53 43 26 30 7 0 70 69 51 44 25 2 Chemistry abnormalities Creatinine increased Bilirubin increased AST increased 38 30 25 1 2 3 17 15 23 1 0 <1 Based on laboratory measurements per IWCLL criteria. Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials (Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. INNOVATE included 150 patients with treatment naïve or previously treated WM who received IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who received IMBRUVICA after failure of prior rituximab-containing therapy. The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and nausea. Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reaction leading to discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in 14% of patients. Study 1118 and INNOVATE Monotherapy Arm Adverse reactions and laboratory abnormalities described below in Table 15 and Table 16 reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm. Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94) Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%) Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Gastroesophageal reflux disease 38 21 15 12 12 2 0 0 1 0 Skin and subcutaneous tissue disorders Bruising* Rash* 28 21 1 1 Vascular disorders Hemorrhage* Hypertension* 28 14 0 4 General disorders and administrative site conditions Fatigue Pyrexia 18 12 2 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain* Muscle spasms 21 19 0 0 Infections and infestations Upper respiratory tract infection Skin infection* Sinusitis* Pneumonia* 19 18 16 13 0 3 0 5 Nervous system disorders Headache Dizziness 14 13 0 0 Respiratory, thoracic and mediastinal disorders Cough 13 0 The body system and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94) Percent of Patients (N=94) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 38 11 Neutrophils Decreased 43 16 Hemoglobin Decreased 21 6 Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients. INNOVATE Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE. Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with WM in INNOVATE Body System Adverse Reaction IMBRUVICA + R (N=75) Placebo + R (N=75) All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%) Skin and subcutaneous tissue disorders Bruising* 37 1 5 0 Rash* 24 1 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 35 4 21 3 Arthralgia 24 3 11 1 Muscle spasms 17 0 12 1 Vascular disorders Hemorrhage* 32 3 17 4 † Hypertension* 20 13 5 4 Gastrointestinal disorders Diarrhea 28 0 15 1 Nausea 21 0 12 0 Dyspepsia 16 0 1 0 Constipation 13 1 11 1 Infections and infestations Pneumonia* 19 13 5 3 Skin infection* 17 3 3 0 Urinary tract infection 13 0 0 0 Bronchitis 12 3 7 0 Influenza 12 0 7 1 Viral upper respiratory tract infection 11 0 7 0 General disorders and administration site conditions Peripheral edema 17 0 12 1 Respiratory, thoracic, and mediastinal disorders Cough 17 0 11 0 Blood and lymphatic system disorders Neutropenia* 16 12 11 4 Cardiac disorders Atrial fibrillation 15 12 3 1 Nervous system disorders Dizziness 11 0 7 0 Psychiatric disorders Insomnia 11 0 4 0 Metabolism and nutrition disorders Hypokalemia 11 0 1 1 The body system and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. † Includes one event with a fatal outcome. Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR. Chronic Graft versus Host Disease Study 1129 The data described below reflect exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy [see Clinical Studies ( 14.3 )] . The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3. Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients. Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect exposure to IMBRUVICA with a median duration of 4.4 months in Study 1129. Table 18: Non-Hematologic Adverse Reactions in ≥ 10% of Adult Patients with cGVHD in Study 1129 (N=42) Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%) General disorders and administration site conditions Fatigue Pyrexia Edema peripheral 57 17 12 12 5 0 Skin and subcutaneous tissue disorders Bruising* Rash* 40 12 0 0 Gastrointestinal disorders Diarrhea Stomatitis* Nausea Constipation 36 29 26 12 10 2 0 0 Musculoskeletal and connective tissue disorders Muscle spasms Musculoskeletal pain* 29 14 2 5 Vascular disorders Hemorrhage* 26 0 Infections and infestations Pneumonia* Upper respiratory tract infection Sepsis* 21 19 10 14 † 0 10 Nervous system disorders Headache 17 5 Injury, poisoning and procedural complications Fall 17 0 Respiratory, thoracic and mediastinal disorders Cough Dyspnea 14 12 0 2 Metabolism and nutrition disorders Hypokalemia 12 7 The system organ class and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. † Includes 2 events with a fatal outcome. Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Adult Patients with cGVHD in Study 1129 (N=42) Percent of Patients (N=42) All Grades (%) Grade 3 or 4 (%) Platelets decreased 33 0 Neutrophils decreased 10 10 Hemoglobin decreased 24 2 Treatment-emergent Grade 4 neutropenia occurred in 2% of patients. iMAGINE The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m 2 orally once daily [see Clinical Studies ( 14.3 )] . The median duration of exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months). Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis. Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis and acute respiratory distress syndrome (ARDS). Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of patients. Adverse reactions which resulted in permanent discontinuation in at least two patients included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dose reduction in at least two patients included stomatitis. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache. Table 20 summarizes the adverse reactions in iMAGINE. Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who Received IMBRUVICA in iMAGINE IMBRUVICA (N=47) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Pyrexia 30 11 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 30 2 Osteonecrosis 11 9 Gastrointestinal disorders Diarrhea 28 2 Abdominal pain* 23 4 Stomatitis* 23 9 Vomiting 19 2 Nausea 19 4 Infections and infestations Pneumonia* 23 13 Skin infection* 17 4 Sepsis* 11 9 † Nervous system disorders Headache 21 2 Skin and subcutaneous tissue disorders Rash* 19 2 Pruritus 13 0 Petechiae 13 0 Respiratory, thoracic and mediastinal disorders Cough 19 2 Vascular disorders Hemorrhage* 17 0 Hypertension* 11 4 Blood and lymphatic system disorders Hypokalemia 15 6 Hypogammaglobulinemia* 11 0 Cardiac Disorders Sinus tachycardia 11 0 Investigations Alanine aminotransferase increased 11 2 The system organ class and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. † Includes 1 fatal outcome. Table 21 summarizes the laboratory abnormalities in iMAGINE. Table 21: Select Hematologic Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with Previously Treated cGVHD Who Received IMBRUVICA in iMAGINE IMBRUVICA (N=47) All Grades (%) Grade 3 or 4 (%) Hemoglobin decreased 49 13 Platelets decreased 21 4 Neutrophils decreased 13 6 Treatment-emergent Grade 4 neutropenia occurred in 3% of patients. Additional Important Adverse Reactions Cardiovascular Events Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. The incidence of atrial fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of cardiac failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm. The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke, cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively. Diarrhea In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm. Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus 89% had complete resolution, and 15% versus 11% had not reported resolution at time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control arm, respectively. Visual Disturbance In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and < 1% Grade 2 and 3). Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had complete resolution and 40% versus 29% had not reported resolution at the time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IMBRUVICA-treated subjects compared to …

Lactation : Advise not to breastfeed ( 8.2 ). Hepatic Impairment : Avoid use of IMBRUVICA in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose ( 2.4 , 8.6 ).

8.1 Pregnancy Risk Summary IMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities (see Data) . Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily. Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily.

8.2 Lactation Risk Summary There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month following the last dose.

8.4 Pediatric Use Chronic GVHD The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older. Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which included pediatric patients age 1 year and older with previously treated cGVHD, including patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2 years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age. Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.3 )] . The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based on body-surface area (BSA) [see Dosage and Administration ( 2.1 )] . The safety and effectiveness of IMBRUVICA have not been established for this indication in pediatric patients less than 1 year of age. Mature B-cell Non-Hodgkin Lymphoma The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were assessed but have not been established based on an open-label, randomized study (NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years, with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for futility. In the randomized population, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm. CLL/SLL, CLL/SLL with 17p deletion, WM The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, or WM.

8.5 Geriatric Use Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62% were ≥ 65 years of age, while 22% were ≥ 75 years of age [see Clinical Studies ( 14.1 , 14.2 , 14.3 )] . No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA [see Adverse Reactions ( 6.1 )] .

8.6 Hepatic Impairment Adult Patients with B-cell Malignancies Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria. Reduce the recommended dose when administering IMBRUVICA to patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for adverse reactions of IMBRUVICA [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )]. Patients with cGVHD Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Dosage and Administration ( 2.4 )] .

8.7 Plasmapheresis Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.

12.1 Mechanism of Action Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro .

12.2 Pharmacodynamics In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg). In adult patients with cGVHD, 93% occupancy of the BTK active site in peripheral blood mononuclear cells was observed at the ibrutinib recommended dose. The mean BTK occupancy in pediatric patients ranged from 95.1% to 99.6%. In vitro Platelet Aggregation Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at 4.6 µM (2026 ng/mL), 0.8 µM (352 ng/mL), and 3 µM (1321 ng/mL) in blood samples from healthy donors, donors taking warfarin, and donors with severe renal dysfunction, respectively. Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP, arachidonic acid, ristocetin, and TRAP-6. Cardiac Electrophysiology At a single dose 4 times the maximum recommended dose (1680 mg), IMBRUVICA did not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC (% coefficient of variation) observed in patients at 420 mg with CLL/SLL is 708 (71%) ng×h/mL, with WM is 707 (72%) ng×h/mL, and in adult patients with previously treated cGVHD is 1159 (50%) ng×h/mL. Steady-state concentrations of ibrutinib without CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple daily doses of 420 mg. Absorption Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy subjects. Ibrutinib is absorbed after oral administration with a median T max of 1 hour to 2 hours. Effect of Food The administration of IMBRUVICA with a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) increased ibrutinib C max by 2- to 4-fold and AUC by approximately 2-fold, compared with administration of ibrutinib after overnight fasting. In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Distribution Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution (V d ) was 683 L, and the apparent volume of distribution at steady state (V d,ss /F) was approximately 10,000 L. Elimination Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and 1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours. Metabolism Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. Excretion Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours, with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the remainder of the excreted dose being metabolites. Specific Populations Age and Sex Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics. Patients with Renal Impairment Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. Patients with Hepatic Impairment The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The C max of ibrutinib increased 5.2-fold in mild hepatic impairment, 8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations ( 8.6 )]. Pediatric Patients In pediatric patients with cGVHD treated with ibrutinib at 240 mg/m 2 once daily (patients age ≥ 1 to < 12 years) or 420 mg once daily (patients age ≥ 12 years), the geometric mean (%CV) steady state AUC and C max in patients age ≥ 1 to < 12 years is 467 (102%) ng×h/mL and 65.7 (96%) ng/mL, respectively, and in patients age ≥ 12 to < 17 years is 966 (78%) ng×h/mL and 149 (79%) ng/mL, respectively. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole (strong CYP3A inhibitor) increased the C max of ibrutinib by 29-fold and AUC by 24-fold. The coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady state C max of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to 10-fold. The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased steady state C max of ibrutinib by 3.4-fold and AUC by 3-fold. Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A inducer) decreased the C max of ibrutinib by more than 13-fold and AUC by more than 10-fold. Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of ibrutinib by 3-fold. In Vitro Studies Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses. Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.

Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC (% coefficient of variation) observed in patients at 420 mg with CLL/SLL is 708 (71%) ng×h/mL, with WM is 707 (72%) ng×h/mL, and in adult patients with previously treated cGVHD is 1159 (50%) ng×h/mL. Steady-state concentrations of ibrutinib without CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple daily doses of 420 mg. Absorption Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy subjects. Ibrutinib is absorbed after oral administration with a median T max of 1 hour to 2 hours. Effect of Food The administration of IMBRUVICA with a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) increased ibrutinib C max by 2- to 4-fold and AUC by approximately 2-fold, compared with administration of ibrutinib after overnight fasting. In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Distribution Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution (V d ) was 683 L, and the apparent volume of distribution at steady state (V d,ss /F) was approximately 10,000 L. Elimination Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and 1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours. Metabolism Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. Excretion Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours, with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the remainder of the excreted dose being metabolites. Specific Populations Age and Sex Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics. Patients with Renal Impairment Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. Patients with Hepatic Impairment The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The C max of ibrutinib increased 5.2-fold in mild hepatic impairment, 8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations ( 8.6 )]. Pediatric Patients In pediatric patients with cGVHD treated with ibrutinib at 240 mg/m 2 once daily (patients age ≥ 1 to < 12 years) or 420 mg once daily (patients age ≥ 12 years), the geometric mean (%CV) steady state AUC and C max in patients age ≥ 1 to < 12 years is 467 (102%) ng×h/mL and 65.7 (96%) ng/mL, respectively, and in patients age ≥ 12 to < 17 years is 966 (78%) ng×h/mL and 149 (79%) ng/mL, respectively. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole (strong CYP3A inhibitor) increased the C max of ibrutinib by 29-fold and AUC by 24-fold. The coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady state C max of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to 10-fold. The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased steady state C max of ibrutinib by 3.4-fold and AUC by 3-fold. Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A inducer) decreased the C max of ibrutinib by more than 13-fold and AUC by more than 10-fold. Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of ibrutinib by 3-fold. In Vitro Studies Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses. Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.