ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS 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 )] Cytopenias [see Warnings and Precautions 5.3 )] Cardiac Arrhythmias and Cardiac Failure [see Warnings and Precautions 5.4 )] Hypertension [see Warnings and Precautions 5.5 )] Second Primary Malignancies [see Warnings and Precautions 5.6 )] Tumor Lysis Syndrome [see Warnings and Precautions 5.7 )] Hemorrhage [see Warnings and Precautions 5.1 )] Infections [see Warnings and Precautions 5.2 )] Cytopenias [see Warnings and Precautions 5.3 )] Cardiac Arrhythmias and Cardiac Failure [see Warnings and Precautions 5.4 )] Hypertension [see Warnings and Precautions 5.5 )] Second Primary Malignancies [see Warnings and Precautions 5.6 )] Tumor Lysis Syndrome [see Warnings and Precautions 5.7 )] The most common (>=30%) adverse reactions in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising (6). The most common (>=20%) adverse reactions in patients with cGVHD are fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia, and pneumonia (6).To report SUSPECTED ADVERSE REACTIONS, contact Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common (>=30%) adverse reactions in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising (6). The most common (>=20%) adverse reactions in patients with cGVHD are fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia, and pneumonia (6).. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.The data in the WARNINGS AND PRECAUTIONS reflect exposure to IMBRUVICA in trials as single agent at 420 mg orally once daily in 475 patients and at 560 mg orally once daily in 174 patients and in trials administered in combination with other drugs at 420 mg orally once daily in 827 patients. Among these 1,476 patients with B-cell malignancies who received IMBRUVICA, 87% were exposed for months or longer and 68% were exposed for greater than one year. In this pooled safety population of 1,476 patients with B-cell malignancies, the most common adverse reactions (>=30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.Mantle Cell LymphomaThe data described below reflect exposure to IMBRUVICA in clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with median treatment duration of 8.3 months.The most common adverse reactions (>= 20%) 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 Table and Table 2).The most common Grade or non-hematological adverse reactions (>= 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to times the upper limit of normal (ULN) occurred in 9% of patients.Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at rate of >= 10% are presented in Table 1.Table 1: Non-Hematologic Adverse Reactions in >= 10% of Patients with MCL (N=111)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaNauseaConstipationAbdominal painVomitingStomatitisDyspepsia513125242317115005010General disorders and administration site conditionsFatigue415Peripheral edema353Pyrexia181Asthenia143Musculoskeletal and connective tissue disordersMusculoskeletal painMuscle spasmsArthralgia371411100Infections and infestationsUpper respiratory tract infectionUrinary tract infectionPneumoniaSkin infectionsSinusitis3414141413038+ 51Skin and subcutaneous tissue disordersBruising Rash Petechiae302511030Respiratory, thoracic and mediastinal disordersDyspnea275+ Cough190Epistaxis110Metabolism and nutrition disordersDecreased appetiteDehydration211224Nervous system disordersDizzinessHeadache141300+ Includes one event with fatal outcome.Table 2: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MCL (N=111)Percent of Patients (N=111)All Grades (%)Grade or (%)Platelets decreased5717Neutrophils decreased4729Hemoglobin decreased419 Based on laboratory measurements and adverse reactionsTreatment-emergent Grade thrombocytopenia (6%) and neutropenia (13%) occurred in patients.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.Patients with MCL who develop lymphocytosis greater than 400,000/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 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.Chronic Lymphocytic Leukemia/Small Lymphocytic LymphomaThe 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 ULN, or total bilirubin >= 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT 3 ULN or total bilirubin 2.5 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 naive 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 naive 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 1102Adverse 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 rate of >= 10% with median duration of treatment of 15.6 months are presented in Table and Table 4.Table 3: Non-Hematologic Adverse Reactions in >= 10% of Patients with CLL/SLL (N=51) in Study 1102Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaConstipationNauseaStomatitisVomitingAbdominal painDyspepsia 592220201814124220200Skin and subcutaneous tissue disordersBruising Rash Petechiae512516200Infections and infestationsUpper respiratory tract infectionSinusitisSkin infectionPneumoniaUrinary tract infection4722161212266102General disorders and administration site conditionsFatiguePyrexia Peripheral edemaAstheniaChills332422141262060Musculoskeletal and connective tissue disordersMusculoskeletal painArthralgiaMuscle spasms252418602Respiratory, thoracic and mediastinal disordersCoughOropharyngeal painDyspnea221412000Nervous system disordersDizzinessHeadache201802Vascular disordersHypertension168Metabolism and nutrition disordersDecreased appetite162Neoplasms benign, malignant, unspecifiedSecond malignancies102+ +One patient death due to histiocytic sarcoma.Table 4: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102Percent of Patients (N=51)All Grades (%)Grade or (%)Platelets decreased6912Neutrophils decreased5326Hemoglobin decreased430 Based on laboratory measurements per IWCLL criteria and adverse reactions.Treatment-emergent Grade thrombocytopenia (8%) and neutropenia (12%) occurred in patients.RESONATEAdverse reactions and laboratory abnormalities described below in Table and Table reflect exposure to IMBRUVICA with median duration of 8.6 months and exposure to ofatumumab with median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.Table 5: Adverse Reactions Reported in >= 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATEBody SystemAdverse ReactionIMBRUVICA(N=195)Ofatumumab(N=191)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Gastrointestinal disordersDiarrhea484182Nausea262180Stomatitis17161Constipation15090Vomiting14061Musculoskeletal and connective tissue disordersMusculoskeletal pain282181Arthralgia17170Muscle spasms13080Skin and subcutaneous tissue disordersRash243130Petechiae14010Bruising12010General disorders and administration site conditionsPyrexia242152+ Respiratory, thoracic and mediastinal disorders Cough190231 Dyspnea122101Infections and infestationsUpper respiratory tract infection161112+ Pneumonia1512+ 1310+ Sinusitis11160Urinary tract infection10451Nervous system disordersHeadache14160Dizziness11050Injury, poisoning and procedural complicationsContusion11030Eye disordersVision blurred10030The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms Includes events of pneumonia with fatal outcome in each arm, and event of pyrexia and upper respiratory tract infection with fatal outcome in the ofatumumab arm.Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATEIMBRUVICA(N=195)Ofatumumab(N=191)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Neutrophils decreased51235726Platelets decreased5254510Hemoglobin decreased360210Treatment-emergent Grade 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-2Adverse reactions and laboratory abnormalities described below in Table and Table reflect exposure to IMBRUVICA with median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2.Table 7: Adverse Reactions Reported in >= 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2Body SystemAdverse ReactionIMBRUVICA(N=135)Chlorambucil(N=132)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Gastrointestinal disorders Diarrhea424170 Nausea221391 Constipation161160 Stomatitis14141 Vomiting130201 Abdominal pain133111 Dyspepsia11020Musculoskeletal and connective tissue disorders Musculoskeletal pain364200 Arthralgia16171 Muscle spasms11050General disorders and administration site conditions Fatigue301385 Peripheral edema19190 Pyrexia170142Respiratory, thoracic and mediastinal disorders Cough220150 Dyspnea101100Skin and subcutaneous tissue disorders Rash214122 Bruising19070Eye disorders Dry eye17050 Lacrimation increased13060 Vision blurred13080 Visual acuity reduced11020Infections and infestations Upper respiratory tract infection172172 Skin infection15 231 Pneumonia14874 Urinary tract infections10181Vascular disorders Hypertension14 410Nervous system disorders Headache 121102 Dizziness110121Investigations Weight decreased100120Subjects with multiple events for 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 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE-2IMBRUVICA(N=135)Chlorambucil(N=132)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Neutrophils Decreased55286731Platelets Decreased4775814Hemoglobin Decreased360392Treatment-emergent Grade 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.HELIOSAdverse reactions described below in Table reflect exposure to IMBRUVICA BR with median duration of 14.7 months and exposure to placebo BR with median of 12.8 months in HELIOS in patients with previously treated CLL/SLL.Table 9: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOSBody SystemAdverse ReactionIMBRUVICA BR(N=287)Placebo BR(N=287)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Blood and lymphatic system disordersNeutropenia66616056+ Thrombocytopenia34162616Gastrointestinal disorders Diarrhea362231 Abdominal pain1218<1Skin and subcutaneous tissue disorders Rash 324251 Bruising 20<18<1Musculoskeletal and connective tissue disorders Musculoskeletal pain292200 Muscle spasms12<150General disorders and administration site conditions Pyrexia254222Vascular disorders Hemorrhage192+ 91 Hypertension 11552Infections and infestations Bronchitis132103 Skin infection 10362Metabolism and nutrition disorders Hyperuricemia10260The 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 and below 0.5%+ Includes events of hemorrhage with fatal outcome in the IMBRUVICA arm and event of neutropenia with 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 and atrial fibrillation was 3% in patients treated with IMBRUVICA BR and 1% in patients treated with placebo BR.iLLUMINATEAdverse reactions described below in Table 10 reflect exposure to IMBRUVICA obinutuzumab with median duration of 29.3 months and exposure to chlorambucil obinutuzumab with median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.Table 10: Adverse Reactions Reported in at Least 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATEBody SystemAdverse ReactionIMBRUVICA Obinutuzumab(N=113)Chlorambucil +Obinutuzumab(N=115)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Blood and lymphatic system disorders Neutropenia48396448 Thrombocytopenia36192811 Anemia174258Skin and subcutaneous tissue disorders Rash363110 Bruising32330Gastrointestinal disorders Diarrhea343100 Constipation160121 Nausea120300Musculoskeletal and connective tissue disorders Musculoskeletal pain331233 Arthralgia221100 Muscle spasms13060Respiratory, thoracic and mediastinal disorders Cough271120Injury, poisoning and procedural complications Infusion related reaction252588Vascular disorders Hemorrhage25190 Hypertension17443General disorders and administration site conditions Pyrexia192261 Fatigue180172 Peripheral edema12070Infections and infestations Pneumonia16994+ Upper respiratory tract 14160 infection Skin infection13130 Urinary tract infection12371 Nasopharyngitis12030 Conjunctivitis11020Metabolism and nutrition disorders Hyperuricemia13100Cardiac disorders Atrial fibrillation12500Psychiatric disorders Insomnia12040The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms+ Includes one event with fatal outcome. E1912Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA rituximab with median duration of 34.3 months and exposure to FCR with median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger. Table 11: Adverse Reactions Reported in at Least 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912Body SystemAdverse ReactionIMBRUVICA Rituximab(N=352)Fludarabine Cyclophosphamide Rituximab(N=158)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)General disorders and administration site conditions Fatigue802783 Peripheral edema281170 Pyrexia271271 Pain23280Musculoskeletal and connective tissue disorders Musculoskeletal pain615352 Arthralgia415101Gastrointestinal disorders Diarrhea534271 Nausea401641 Stomatitis22181 Abdominal pain192101 Vomiting182280 Constipation170320Skin and subcutaneous tissue disorders Rash494295 Bruising36141Vascular disorders Hypertension4219226 Hemorrhage31281Nervous system disorders Headache401271 Dizziness211131 Peripheral neuropathy191131Respiratory, thoracic and mediastinal disorders Cough320250 Dyspnea222211Infections and infestations Upper respiratory tract 291192 infection Skin infection16131Metabolism and nutrition disorders Hyperuricemia19140 Decreased appetite150201Psychiatric disorders Insomnia161191The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR termsTable 12: 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 or 4(%)All Grades(%)Grade or 4(%)Hematology abnormalities Neutrophils decreased Platelets decreased Hemoglobin decreased534326307070695144252Chemistry abnormalities Creatinine increased Bilirubin increased AST increased38302512317152310<1Based on laboratory measurements per IWCLL criteriaWaldenstroms Macroglobulinemia and Marginal Zone LymphomaThe data described below reflect exposure to IMBRUVICA in three single-arm open-label clinical trials (Study 1118, Study 1121, and INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM or MZL, including total n=307 patients overall and n=232 patients exposed to IMBRUVICA. Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. Study 1121 included 63 patients with previously treated MZL who received single agent IMBRUVICA. INNOVATE included 150 patients with treatment naive 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 failed prior rituximab-containing therapy and received IMBRUVICA.The most common adverse reactions in Studies 1118, 1121, and INNOVATE (>= 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia, rash, fatigue, and nausea.Seven percent of patients receiving IMBRUVICA across Studies 1118, 1121, and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 13% of patients.Study 1118 and INNOVATE Monotherapy ArmAdverse reactions and laboratory abnormalities described below in Table 13 and Table 14 reflect exposure to IMBRUVICA with median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.Table 13: Non-Hematologic Adverse Reactions in >= 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaNauseaStomatitisConstipationGastroesophageal reflux disease382115121220010Skin and subcutaneous tissue disordersBruisingRash282111Vascular disordersHemorrhageHypertension281404General disorders and administrative site conditionsFatiguePyrexia181222Musculoskeletal and connective tissue disordersMusculoskeletal painMuscle spasms211900Infections and infestationsUpper respiratory tract infectionSkin infectionSinusitisPneumonia191816130305Nervous system disordersHeadacheDizziness141300Respiratory, thoracic and mediastinal disordersCough130The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.Table 14: 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 or (%)Platelets Decreased3811Neutrophils Decreased4316Hemoglobin Decreased216Treatment-emergent Grade thrombocytopenia (4%) and neutropenia (7%) occurred in patients. INNOVATEAdverse reactions described below in Table 15 reflect exposure to IMBRUVICA R with median duration of 25.8 months and exposure to placebo R with median duration of 15.5 months in patients with treatment naive or previously treated WM in INNOVATE. Table 15: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with WM in INNOVATEBody SystemAdverse ReactionIMBRUVICA R(N=75)Placebo R(N=75)All Grades(%)Grade or Higher(%)All Grades(%)Grade or Higher(%)Skin and subcutaneous tissue disorders Bruising37150 Rash241110Musculoskeletal and connective tissue disorders Musculoskeletal pain354213 Arthralgia243111 Muscle spasms170121Vascular disorders Hemorrhage323174+ Hypertension201354Gastrointestinal disorders Diarrhea280151 Nausea210120 Dyspepsia16010 Constipation131111Infections and infestations Pneumonia191353 Skin infection17330 Urinary tract infection13000 Bronchitis12370 Influenza12071Viral upper respiratory tract infection11070General disorders and administration site conditions Peripheral edema170121Respiratory, thoracic, and mediastinal disorders Cough170110Blood and lymphatic system disorders Neutropenia1612114Cardiac disorders Atrial fibrillation151231Nervous system disorders Dizziness11070Psychiatric disorders Insomnia11040Metabolism and nutrition disorders Hypokalemia11011The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes one event with fatal outcome. Grade or infusion related reactions were observed in 1% of patients treated with IR.Study 1121Adverse reactions and laboratory abnormalities described below in Table 16 and Table 17 reflect exposure to IMBRUVICA with median duration of 11.6 months in Study 1121.Table 16: Non-Hematologic Adverse Reactions in >= 10% in Patients with MZL in Study 1121 (N=63)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)General disorders and administrative site conditionsFatiguePeripheral edemaPyrexia442417622Gastrointestinal disordersDiarrheaNauseaDyspepsiaStomatitisAbdominal painConstipationAbdominal pain upperVomiting432519171614131150022002Skin and subcutaneous tissue disordersBruising Rash Pruritus 412914050Musculoskeletal and connective tissue disordersMusculoskeletal painArthralgiaMuscle spasms402419323Infections and infestationsUpper respiratory tract infectionSinusitisBronchitisPneumonia2119111100010Metabolism and nutrition disordersDecreased appetiteHyperuricemiaHypoalbuminemiaHypokalemia161614132000Vascular disordersHemorrhageHypertension30142+ 5Respiratory, thoracic and mediastinal disordersCoughDyspnea222122Nervous system disordersDizzinessHeadache191300Psychiatric disordersAnxiety162The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes one event with fatal outcome.Table 17: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63)Percent of Patients (N=63)All Grades (%)Grade or (%)Platelets decreased496Hemoglobin decreased4313Neutrophils decreased2213Treatment-emergent Grade thrombocytopenia (3%) and neutropenia (6%) occurred in patients.Chronic Graft versus Host DiseaseThe 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.The most common adverse reactions in the cGVHD trial (>= 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 the cGVHD trial 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 median duration of 4.4 months in the cGVHD trial.Table 18: Non-Hematologic Adverse Reactions in >= 10% of Patients with cGVHD (N=42)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)General disorders and administration site conditionsFatiguePyrexiaEdema peripheral5717121250Skin and subcutaneous tissue disordersBruisingRash401200Gastrointestinal disordersDiarrheaStomatitisNauseaConstipation3629261210200Musculoskeletal and connective tissue disordersMuscle spasmsMusculoskeletal pain291425Vascular disordersHemorrhage260Infections and infestationsPneumoniaUpper respiratory tract infectionSepsis21191014+ 010Nervous system disordersHeadache175Injury, poisoning and procedural complicationsFall170Respiratory, thoracic and mediastinal disordersCoughDyspnea141202Metabolism and nutrition disordersHypokalemia 12 The system organ class and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes events with fatal outcome. Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42)Percent of Patients (N=42)All Grades (%)Grade or (%)Platelets decreased330Neutrophils decreased1010Hemoglobin decreased242Treatment-emergent Grade neutropenia occurred in 2% of patients.Additional Important Adverse ReactionsCardiovascular EventsData 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 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 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 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 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively. DiarrheaIn 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 rate of 43% of patients treated with IMBRUVICA compared to 19% of patients in the control arm. Grade 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, to 708) versus 46 days (range, to 492) for any grade diarrhea and 117 days (range, to 414) versus 194 days (range, 11 to 325) for Grade 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 days (range, to 655) versus days (range, to 367) for any grade diarrhea and days (range, to 78) versus 19 days (range, to 56) for Grade diarrhea in IMBRUVICA-treated subjects compared to the control arm, respectively. Visual DisturbanceIn 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 or higher) compared to 6% in the control arm (5% Grade and <1% Grade and 3). Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, to 617) versus 100 days (range, 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, to 457) versus 26 days (range, to 721) in IMBRUVICA-treated subjects compared to the control arm, respectively. Long-Term SafetyThe safety data from long-term treatment with IMBRUVICA over years of 1,284 patients (treatment-naive CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) were analyzed. The median treatment duration was 51 months (range, 0.2 to 98 months) for CLL/SLL, 11 months (range, to 87 months) for MCL, and 47 months (range, 0.3 to 61 months) for WM. The cumulative rate of hypertension increased over time. The prevalence for Grade 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%. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of IMBRUVICA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis Respiratory disorders: interstitial lung disease Metabolic and nutrition disorders: tumor lysis syndrome Immune system disorders: anaphylactic shock, angioedema, urticaria Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses Infections: hepatitis reactivation Nervous system disorders: peripheral neuropathy. Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis Respiratory disorders: interstitial lung disease Metabolic and nutrition disorders: tumor lysis syndrome Immune system disorders: anaphylactic shock, angioedema, urticaria Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses Infections: hepatitis reactivation Nervous system disorders: peripheral neuropathy.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 28 Capsule Bottle CartonNDC 57962-070-28Imbruvica(R)(ibrutinib) capsules70 mgEach capsule contains: ibrutinib 70 mgSwallow capsules whole with water28 CapsulesRx OnlyPharmacyclics LLCAn AbbVie CompanyJanssen Biotech, Inc.. PRINCIPAL DISPLAY PANEL 28 Capsule Bottle CartonNDC 57962-070-28Imbruvica(R)(ibrutinib) capsules70 mgEach capsule contains: ibrutinib 70 mgSwallow capsules whole with water28 CapsulesRx OnlyPharmacyclics LLCAn AbbVie CompanyJanssen Biotech, Inc.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ibrutinib was not carcinogenic in 6-month rasH2 mouse study at oral doses up to 2000 mg/kg/day resulting in exposures approximately 23 (males) to 37 (females) times higher than the exposure in humans at dose of 560 mg daily [see Warnings and Precautions 5.6 )].Ibrutinib was not mutagenic in bacterial mutagenicity (Ames) assay, was not clastogenic in chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.Rats were administered oral daily doses of ibrutinib for weeks prior to pairing and during pairing in males and weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Ibrutinib is small-molecule inhibitor of BTK. Ibrutinib forms covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTKs 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 vitro Platelet AggregationIbrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at 4.6 uM (2026 ng/mL), 0.8 uM (352 ng/mL), and uM (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 ElectrophysiologyAt single dose 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 (1.5 times the maximum approved recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC (% coefficient of variation) observed in patients at 560 mg with MCL is 865 (69%) ngoh/mL and with MZL is 978 (82%) ngoh/mL, and in patients at 420 mg with CLL/SLL is 708 (71%) ngoh/mL, with WM is 707 (72%) ngoh/mL, and with cGVHD is 1159 (50%) ngoh/mL. Steady-state concentrations of ibrutinib without CYP3A inhibitors were achieved with an accumulation ratio of to 1.6 after week of multiple daily doses of 420 mg or 560 mg.AbsorptionAbsolute 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 median Tmax of hour to hours.Effect of FoodThe administration of IMBRUVICA with 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 Cmax 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 substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).DistributionReversible 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 (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10,000 L.EliminationIntravenous 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 hours to hours.MetabolismMetabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A and to minor extent by CYP2D6. The active metabolite, PCI-45227, is 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 to 2.8.ExcretionIbrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After 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 PopulationsAge and SexAge and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.Patients with Renal ImpairmentMild 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 ImpairmentThe 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 Cmax 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 )]. Drug Interaction StudiesClinical Studies and Model-Informed ApproachesEffect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole (strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady state Cmax 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 Cmax 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 Cmax 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 StudiesEffect 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 with narrow therapeutic index (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. 14.1 Mantle Cell Lymphoma. The safety and efficacy of IMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in Study 1104 (NCT01236391), an open-label, multi-center, single-arm trial of 111 previously treated patients. IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkins lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR).The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were White. At baseline, 89% of patients had baseline ECOG performance status of or 1. The median time since diagnosis was 42 months, and median number of prior treatments was (range, to treatments), including 11% with prior stem cell transplantation. At baseline, 39% of subjects had at least one tumor >= cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening.Responses to IMBRUVICA are shown in Table 20.Table 20: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL in Study 1104Total (N=111)ORR (%)65.895% CI (%)(56.2, 74.5)CR (%)17.1PR (%)48.6Median DOR months (95% CI) 17.5 (15.8, NE)CI confidence interval; CR complete response; PR partial response; NE not evaluableAn Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%.The median time to response was 1.9 months.LymphocytosisUpon initiation of IMBRUVICA, temporary increase in lymphocyte counts (i.e., >= 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of IMBRUVICA therapy and resolves by median of weeks.. 14.2 Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma. The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one uncontrolled trial and five randomized, controlled trials.Study 1102Study 1102 (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously treated CLL patients. IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were White. All patients had baseline ECOG performance status of or 1. The median time since diagnosis was 80 months and the median number of prior treatments was (range, to 12 treatments). At baseline, 46% of subjects had at least one tumor >= cm.The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.RESONATEThe RESONATE study, randomized, multicenter, open-label, phase study of IMBRUVICA versus ofatumumab (NCT01578707), was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by dose of 2000 mg weekly for doses and then every weeks for additional doses. Fifty-seven patients randomized to ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were White. All patients had baseline ECOG performance status of or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was (range, to 13 treatments). At baseline, 58% of patients had at least one tumor >= cm. Thirty-two percent of patients had 17p deletion.Efficacy results for RESONATE are shown in Table 21 and the Kaplan-Meier curves for PFS, assessed by an IRC according to IWCLL criteria, and OS are shown in Figure and Figure 2, respectively. Table 21: Efficacy Results in Patients with CLL/SLL in RESONATEEndpointIMBRUVICAN=195OfatumumabN=196Progression Free SurvivalbNumber of events (%)35 (17.9)111 (56.6) Disease progression2693 Death events918 Median (95% CI), monthsNE8.1 (7.2, 8.3) HR (95% CI)0.22 (0.15, 0.32)Overall Survivala Number of deaths (%)16 (8.2)33 (16.8) HR (95% CI)0.43 (0.24, 0.79)Overall Response Rateb 42.6%4.1%a Median OS not evaluable for either armb IRC evaluated. All partial responses achieved; none of the patients achieved complete response.CI confidence interval; HR hazard ratio; NE not evaluableFigure 1: Kaplan-Meier Curve of Progression Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with CLL/SLL in RESONATE63-Month Follow-UpWith an overall follow-up of 63 months, the median investigator-assessed PFS per IWCLL criteria was 44.1 months [95% CI (38.5, 56.9)] in the IMBRUVICA arm and 8.1 months [95% CI (7.8, 8.3)] in the ofatumumab arm, respectively. Overall response rate as assessed by investigators was 87.2% in the IMBRUVICA arm versus 22.4% in the ofatumumab arm. CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATERESONATE included 127 patients with del 17p CLL/SLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were White. All patients had baseline ECOG performance status of or 1. PFS and ORR were assessed by an IRC. Efficacy results for del 17p CLL/SLL are shown in Table 22.Table 22: Efficacy Results in Patients with del 17p CLL/SLL in RESONATEEndpointIMBRUVICAN=63OfatumumabN=64Progression Free SurvivalaNumber of events (%)16 (25.4)38 (59.4) Disease progression12 31 Death events 7 Median (95% CI), monthsNE5.8 (5.3, 7.9) HR (95% CI)0.25 (0.14, 0.45)Overall Response Ratea 47.6%4.7%a IRC evaluated. All partial responses achieved; none of the patients achieved complete response.CI confidence interval; HR hazard ratio; NE not evaluable63-Month Follow-UpWith an overall follow-up of 63 months, the median investigator-assessed PFS in patients with del 17p per IWCLL criteria was 40.6 months [95% CI (25.4, 44.6)] in the IMBRUVICA arm and 6.2 months [95% CI (4.6, 8.1)] in the ofatumumab arm, respectively. Overall response rate as assessed by investigators in patients with del 17p was 88.9% in the IMBRUVICA arm versus 18.8% in the ofatumumab arm. RESONATE-2The RESONATE-2 study, randomized, multicenter, open-label, phase study of IMBRUVICA versus chlorambucil (NCT01722487), was conducted in patients with treatment naive CLL or SLL who were 65 years of age or older. Patients (n 269) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at starting dose of 0.5 mg/kg on Days and 15 of each 28-day cycle for maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were White. Ninety one percent of patients had baseline ECOG performance status of or and 9% had an ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating CLL therapy include: progressive marrow failure demonstrated by anemia and/or thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).With median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and 21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively]. With 41% of patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT patient population resulted in statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and 2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)] in the IMBRUVICA and chlorambucil arms, respectively.Efficacy results for RESONATE-2 are shown in Table 23 and the Kaplan-Meier curve for PFS, assessed by an IRC according to IWCLL criteria is shown in Figure 3. Table 23: Efficacy Results in Patients with CLL/SLL in RESONATE-2EndpointIMBRUVICAN=136ChlorambucilN=133Progression Free SurvivalaNumber of events (%)15 (11.0)64 (48.1) Disease progression12 57 Death events 7 Median (95% CI), monthsNE18.9 (14.1, 22.0) HRb (95% CI)0.16 (0.09, 0.28)Overall Response Ratea (CR PR) 82.4%35.3% P-value<0.0001a IRC evaluated; Five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved complete responseb HR hazard ratio; NE not evaluableFigure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE-255-Month Follow-UpWith an overall follow-up of 55 months, the median PFS was not reached in the IMBRUVICA arm. HELIOSThe HELIOS study, randomized, double-blind, placebo-controlled phase study of IMBRUVICA in combination with bendamustine and rituximab (BR) (NCT01611090), was conducted in patients with previously treated CLL or SLL. Patients (n 578) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days and 3, and on Cycles 2-6, Days and for up to cycles, and all patients had CLCr >= 40 mL/min at baseline. Rituximab was administered at dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles through 6, Day 1.The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were White. All patients had baseline ECOG performance status of or 1. The median time since diagnosis was 5.9 years and the median number of prior treatments was (range, to 11 treatments). At baseline, 56% of patients had at least one tumor 5 cm and 26% presented with del11q.Efficacy results for HELIOS are shown in Table 24 and the Kaplan-Meier curves for PFS are shown in Figure 4.Table 24: Efficacy Results in Patients with CLL/SLL in HELIOSEndpointIMBRUVICA BRN=289Placebo BRN=289Progression Free Survivala Number of events (%)56 (19.4)183 (63.3) Median (95% CI), monthsNE13.3 (11.3, 13.9) HR (95% CI)0.20 (0.15, 0.28)Overall Response Ratea 82.7%67.8%a IRC evaluated, twenty-four subjects (8.3%) in the IMBRUVICA BR arm and six subjects (2.1%) in the placebo BR arm achieved complete responseBR bendamustine and rituximab; CI confidence interval; HR hazard ratio; NE not evaluableFigure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in HELIOSiLLUMINATEThe iLLUMINATE study, randomized, multi-center, phase study of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab (NCT02264574), was conducted in patients with treatment naive CLL or SLL. Patients were 65 years of age or older or 65 years of age with coexisting medical conditions, reduced renal function as measured by creatinine clearance 70 mL/min, or presence of del 17p/TP53 mutation. Patients (n 229) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity or chlorambucil at dose of 0.5 mg/kg on Days and 15 of each 28-day cycle for cycles. In both arms, patients received 1,000 mg of obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of subsequent cycles (total of cycles, 28 days each). The first dose of obinutuzumab was divided between Day (100 mg) and Day (900 mg). The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were White. All patients had baseline ECOG performance status of (48%) or 1-2 (52%). The trial enrolled 214 patients with CLL and 15 patients with SLL. At baseline, 65% of patients presented with CLL/SLL with high risk factors (del 17p/TP53 mutation [18%], del 11q [15%], or unmutated immunoglobulin heavy-chain variable region (unmutated IGHV) [54%]). The most common reasons for initiating CLL therapy included: lymphadenopathy (38%), night sweats (34%), progressive marrow failure (31%), fatigue (29%), splenomegaly (25%), and progressive lymphocytosis (21%).With median follow-up time on study of 31 months, efficacy results for iLLUMINATE assessed by an IRC according to IWCLL criteria are shown in Table 25, and the Kaplan-Meier curve for PFS is shown in Figure 5.Table 25: Efficacy Results in Patients with CLL/SLL in iLLUMINATEEndpointIMBRUVICA ObinutuzumabN=113Chlorambucil ObinutuzumabN=116Progression Free Survivala Number of events (%)24 (21)74 (64) Disease progression1164 Death events 1310 Median (95% CI), monthsNE19.0 (15.1, 22.1) HR (95% CI)0.23 (0.15, 0.37) P-valueb <0.0001Overall Response Rate (%)a88.573.3 CRc (%)19.57.8 PRd (%)69.065.5a IRC-evaluatedb P-value is from unstratified log-rank testc Includes patient in the IMBRUVICA obinutuzumab arm with complete response with incomplete marrow recovery (CRi)d PR nPR +PRHR hazard ratio; NE not evaluableFigure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in iLLUMINATEIn the high risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), the PFS HR was 0.15 [95% CI (0.09, 0.27)]. E1912The E1912 study, randomized, multi-center, phase study of IMBRUVICA in combination with rituximab versus standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy (NCT02048813), was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL requiring systemic therapy. All patients had CLcr 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n =529) were randomized 2:1 to receive either IMBRUVICA plus rituximab or FCR. IMBRUVICA was administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was administered at dose of 25 mg/m2, and cyclophosphamide was administered at dose of 250 mg/m2, both on Days 1, 2, and of Cycles 1-6. Rituximab was initiated in Cycle for the IMBRUVICA plus rituximab arm and in Cycle for the FCR arm and was administered at 50 mg/m2 on Day of the first cycle, 325 mg/m2 on Day of the first cycle, and 500 mg/m2 on Day of subsequent cycles, for total of cycles. Each cycle was 28 days.The median age was 58 years (range, 28 to 70 years), 67% were male, 90% were White and 98% had ECOG performance status of 0-1. At baseline, 43% of patients were Rai stage or and 59% of patients presented with high risk factors (TP53 mutation [6%], del11q [22%], or unmutated IGHV [53%]).With median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 26. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in Figure 6.Table 26: Efficacy Results in Patients with CLL/SLL in E1912EndpointIMBRUVICA R N=354 FCRN=175Progression Free Survival Number of events (%)41 (12)44 (25) Disease progression3938 Death events 26 Median (95% CI), monthsNE (49.4, NE)NE (47.1, NE) HR (95% CI)0.34 (0.22, 0.52) P-valuea <0.0001a P-value is from unstratified log-rank test.FCR fludarabine, cyclophosphamide, and rituximab; HR hazard ratio; = rituximab; NE not evaluableFigure 6: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in E1912With median follow-up time on study of 49 months, median overall survival was not reached with total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR treatment arms. LymphocytosisUpon initiation of single-agent IMBRUVICA, an increase in lymphocyte counts (i.e., >= 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by median of 14 weeks (range, 0.1 to 104 weeks). When IMBRUVICA was administered in combination, lymphocytosis was 7% with IMBRUVICA BR versus 6% with placebo BR and 7% with IMBRUVICA obinutuzumab versus 1% with chlorambucil obinutuzumab.. 14.3 Waldenstroms Macroglobulinemia. The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-arm trials and one randomized, controlled trial.Study 1118 and INNOVATE Monotherapy ArmStudy 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63 previously treated patients with WM. IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an IRC using criteria adopted from the International Workshop of Waldenstroms Macroglobulinemia. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were White. All patients had baseline ECOG performance status of or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was (range, to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).Responses, defined as partial response or better, per IRC are shown in Table 27.Table 27: Response Rate and Duration of Response (DOR) Based on IRC Assessment in Patients with WM in Study 1118Total (N=63)Response rate (CR+VGPR+PR), (%)61.995% CI (%)(48.8, 73.9)Complete Response (CR)0Very Good Partial Response (VGPR), (%)11.1Partial Response (PR), (%)50.8Median duration of response, months (range) NE (2.8+, 18.8+)CI confidence interval; NE not evaluableThe median time to response was 1.2 months (range, 0.7-13.4 months).The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single-agent IMBRUVICA. The median age was 67 years (range, 47 to 90 years). Eighty-one percent of patients had baseline ECOG performance status of or 1, and 19% had baseline ECOG performance status of 2. The median number of prior treatments was (range, to treatments). With an overall follow-up of 61 months, the response rate observed in the INNOVATE monotherapy arm per IRC assessment was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months (range, 2.4 to 60.2+ months). INNOVATEThe INNOVATE study, randomized, double-blind, placebo-controlled, phase study of IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in treatment naive or previously treated patients with WM. Patients (n 150) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at dose of 375 mg/m2 for consecutive weeks (weeks 1-4) followed by second course of weekly rituximab for consecutive weeks (weeks 17-20). The major efficacy outcome measure is progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response rate. The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were White. Ninety-three percent of patients had baseline ECOG performance status of or 1, and 7% of patients had baseline ECOG performance status of 2. Forty-five percent of patients were treatment naive, and 55% of patients were previously treated. Among previously treated patients, the median number of prior treatments was (range, to treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.An exploratory analysis demonstrated sustained hemoglobin improvement (defined as increase of >= g/dL over baseline for at least weeks without blood transfusions or growth factor support) in 65% of patients in the IMBRUVICA R group and 39% of patients in the placebo R group.With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the final analysis for INNOVATE are shown in Table 28, and the Kaplan-Meier curves for PFS are shown in Figure 7.Table 28: Efficacy Results in Patients with WM by IRC in INNOVATE (Final Analysis)EndpointIMBRUVICA RN=75Placebo RN=75Progression Free Survival Number of events (%)22 (29)50 (67) Median (95% CI), monthsNE (57.7, NE)20.3 (13.0, 27.6) HR (95% CI)0.25 (0.15, 0.42) P-valuea <0.0001Response Rate (CR+VGPR+PR)b76%31% 95% CI (%)(65, 85)(21, 42) Complete Response (CR)1%1% Very Good Partial Response (VGPR)29%4% Partial Response (PR)45%25%Median duration of response, months (range)NE (1.9+, 58.9+)NE (4.6+, 49.7+)CI confidence interval; HR hazard ratio; NE not evaluable; = rituximaba P-value is from the stratified log-rank testb P-value associated with response rate was <0.0001Figure 7: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with WM in INNOVATEMedian overall survival was not reached for either treatment arm. With an overall follow-up of 63 months, (12%) patients on IMBRUVICA R and 10 (13.3%) patients on placebo R had died. Forty-seven percent of patients randomized to the placebo R arm crossed over to receive IMBRUVICA.. 14.4 Marginal Zone Lymphoma. The safety and efficacy of IMBRUVICA in MZL were evaluated in Study 1121 (NCT01980628), an open-label, multi-center, single-arm trial of patients who received at least one prior therapy. IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an IRC using criteria adopted from the International Working Group criteria for malignant lymphoma. The efficacy analysis included 63 patients with sub-types of MZL: mucosa-associated lymphoid tissue (MALT; N=32), nodal (N=17), and splenic (N=14). The median age was 66 years (range, 30 to 92 years), 59% were female, and 84% were White. Ninety two percent of patients had baseline ECOG performance status of or and 8% had ECOG performance status 2. The median time since diagnosis was 3.8 years, and the median number of prior treatments was (range, to treatments).Responses per IRC are shown in Table 29.Table 29: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with MZL in Study 1121Total (N=63)Response rate (CR PR), (%)46.0%95% CI (%)(33.4, 59.1)Complete Response (CR), (%)3.2Partial Response (PR), (%)42.9Median duration of response, months (range) NE (16.7, NE)CI confidence interval; NE not evaluableMedian follow-up time on study 19.4 months The median time to response was 4.5 months (range, 2.3 to 16.4 months). Overall response rates were 46.9%, 41.2%, and 50.0% for the MZL sub-types (MALT, nodal, splenic), respectively.. 14.5 Chronic Graft versus Host Disease. The safety and efficacy of IMBRUVICA in cGVHD were evaluated in Study 1129 (NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after failure of first line corticosteroid therapy and requiring additional therapy. IMBRUVICA was administered orally at 420 mg once daily. The responses were assessed by investigators using the 2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two modifications to align with the updated 2014 NIH Consensus Panel Response Criteria.The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were White. The most common underlying malignancies leading to transplantation were acute lymphocytic leukemia, acute myeloid leukemia, and CLL. The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was (range, to treatments), and 60% of patients had Karnofsky performance score of <= 80. The majority of patients (88 %) had at least organs involved at baseline, with the most commonly involved organs being mouth (86%), skin (81%), and gastrointestinal tract (33%). The median daily corticosteroid dose (prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline. Prophylaxis for infections were managed per institutional guidelines with 79% of patients receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole derivatives.Efficacy results are shown in Table 30.Table 30: Best Overall Response Rate (ORR) and Sustained Response Rate Based on Investigator Assessmenta in Patients with cGVHD in Study 1129Total (N=42)ORR28 (67%) 95% CI (51%, 80%)Complete Response (CR) (21%)Partial Response (PR) 19 (45%)Sustained response rateb 20 (48%) CI confidence interval Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added not evaluable for organs with non-cGVHD abnormalities, and organ score change from to was not considered disease progression) Sustained response rate is defined as the proportion of patients who achieved CR or PR that was sustained for at least 20 weeks.The median time to response coinciding with the first scheduled response assessment was 12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for cGVHD (skin, mouth, gastrointestinal tract, and liver).ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42) of patients on at least consecutive visits.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.The data in the WARNINGS AND PRECAUTIONS reflect exposure to IMBRUVICA in trials as single agent at 420 mg orally once daily in 475 patients and at 560 mg orally once daily in 174 patients and in trials administered in combination with other drugs at 420 mg orally once daily in 827 patients. Among these 1,476 patients with B-cell malignancies who received IMBRUVICA, 87% were exposed for months or longer and 68% were exposed for greater than one year. In this pooled safety population of 1,476 patients with B-cell malignancies, the most common adverse reactions (>=30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.Mantle Cell LymphomaThe data described below reflect exposure to IMBRUVICA in clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with median treatment duration of 8.3 months.The most common adverse reactions (>= 20%) 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 Table and Table 2).The most common Grade or non-hematological adverse reactions (>= 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to times the upper limit of normal (ULN) occurred in 9% of patients.Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at rate of >= 10% are presented in Table 1.Table 1: Non-Hematologic Adverse Reactions in >= 10% of Patients with MCL (N=111)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaNauseaConstipationAbdominal painVomitingStomatitisDyspepsia513125242317115005010General disorders and administration site conditionsFatigue415Peripheral edema353Pyrexia181Asthenia143Musculoskeletal and connective tissue disordersMusculoskeletal painMuscle spasmsArthralgia371411100Infections and infestationsUpper respiratory tract infectionUrinary tract infectionPneumoniaSkin infectionsSinusitis3414141413038+ 51Skin and subcutaneous tissue disordersBruising Rash Petechiae302511030Respiratory, thoracic and mediastinal disordersDyspnea275+ Cough190Epistaxis110Metabolism and nutrition disordersDecreased appetiteDehydration211224Nervous system disordersDizzinessHeadache141300+ Includes one event with fatal outcome.Table 2: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MCL (N=111)Percent of Patients (N=111)All Grades (%)Grade or (%)Platelets decreased5717Neutrophils decreased4729Hemoglobin decreased419 Based on laboratory measurements and adverse reactionsTreatment-emergent Grade thrombocytopenia (6%) and neutropenia (13%) occurred in patients.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.Patients with MCL who develop lymphocytosis greater than 400,000/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 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.Chronic Lymphocytic Leukemia/Small Lymphocytic LymphomaThe 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 ULN, or total bilirubin >= 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT 3 ULN or total bilirubin 2.5 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 naive 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 naive 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 1102Adverse 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 rate of >= 10% with median duration of treatment of 15.6 months are presented in Table and Table 4.Table 3: Non-Hematologic Adverse Reactions in >= 10% of Patients with CLL/SLL (N=51) in Study 1102Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaConstipationNauseaStomatitisVomitingAbdominal painDyspepsia 592220201814124220200Skin and subcutaneous tissue disordersBruising Rash Petechiae512516200Infections and infestationsUpper respiratory tract infectionSinusitisSkin infectionPneumoniaUrinary tract infection4722161212266102General disorders and administration site conditionsFatiguePyrexia Peripheral edemaAstheniaChills332422141262060Musculoskeletal and connective tissue disordersMusculoskeletal painArthralgiaMuscle spasms252418602Respiratory, thoracic and mediastinal disordersCoughOropharyngeal painDyspnea221412000Nervous system disordersDizzinessHeadache201802Vascular disordersHypertension168Metabolism and nutrition disordersDecreased appetite162Neoplasms benign, malignant, unspecifiedSecond malignancies102+ +One patient death due to histiocytic sarcoma.Table 4: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102Percent of Patients (N=51)All Grades (%)Grade or (%)Platelets decreased6912Neutrophils decreased5326Hemoglobin decreased430 Based on laboratory measurements per IWCLL criteria and adverse reactions.Treatment-emergent Grade thrombocytopenia (8%) and neutropenia (12%) occurred in patients.RESONATEAdverse reactions and laboratory abnormalities described below in Table and Table reflect exposure to IMBRUVICA with median duration of 8.6 months and exposure to ofatumumab with median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.Table 5: Adverse Reactions Reported in >= 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATEBody SystemAdverse ReactionIMBRUVICA(N=195)Ofatumumab(N=191)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Gastrointestinal disordersDiarrhea484182Nausea262180Stomatitis17161Constipation15090Vomiting14061Musculoskeletal and connective tissue disordersMusculoskeletal pain282181Arthralgia17170Muscle spasms13080Skin and subcutaneous tissue disordersRash243130Petechiae14010Bruising12010General disorders and administration site conditionsPyrexia242152+ Respiratory, thoracic and mediastinal disorders Cough190231 Dyspnea122101Infections and infestationsUpper respiratory tract infection161112+ Pneumonia1512+ 1310+ Sinusitis11160Urinary tract infection10451Nervous system disordersHeadache14160Dizziness11050Injury, poisoning and procedural complicationsContusion11030Eye disordersVision blurred10030The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms Includes events of pneumonia with fatal outcome in each arm, and event of pyrexia and upper respiratory tract infection with fatal outcome in the ofatumumab arm.Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATEIMBRUVICA(N=195)Ofatumumab(N=191)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Neutrophils decreased51235726Platelets decreased5254510Hemoglobin decreased360210Treatment-emergent Grade 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-2Adverse reactions and laboratory abnormalities described below in Table and Table reflect exposure to IMBRUVICA with median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2.Table 7: Adverse Reactions Reported in >= 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2Body SystemAdverse ReactionIMBRUVICA(N=135)Chlorambucil(N=132)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Gastrointestinal disorders Diarrhea424170 Nausea221391 Constipation161160 Stomatitis14141 Vomiting130201 Abdominal pain133111 Dyspepsia11020Musculoskeletal and connective tissue disorders Musculoskeletal pain364200 Arthralgia16171 Muscle spasms11050General disorders and administration site conditions Fatigue301385 Peripheral edema19190 Pyrexia170142Respiratory, thoracic and mediastinal disorders Cough220150 Dyspnea101100Skin and subcutaneous tissue disorders Rash214122 Bruising19070Eye disorders Dry eye17050 Lacrimation increased13060 Vision blurred13080 Visual acuity reduced11020Infections and infestations Upper respiratory tract infection172172 Skin infection15 231 Pneumonia14874 Urinary tract infections10181Vascular disorders Hypertension14 410Nervous system disorders Headache 121102 Dizziness110121Investigations Weight decreased100120Subjects with multiple events for 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 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE-2IMBRUVICA(N=135)Chlorambucil(N=132)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Neutrophils Decreased55286731Platelets Decreased4775814Hemoglobin Decreased360392Treatment-emergent Grade 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.HELIOSAdverse reactions described below in Table reflect exposure to IMBRUVICA BR with median duration of 14.7 months and exposure to placebo BR with median of 12.8 months in HELIOS in patients with previously treated CLL/SLL.Table 9: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOSBody SystemAdverse ReactionIMBRUVICA BR(N=287)Placebo BR(N=287)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Blood and lymphatic system disordersNeutropenia66616056+ Thrombocytopenia34162616Gastrointestinal disorders Diarrhea362231 Abdominal pain1218<1Skin and subcutaneous tissue disorders Rash 324251 Bruising 20<18<1Musculoskeletal and connective tissue disorders Musculoskeletal pain292200 Muscle spasms12<150General disorders and administration site conditions Pyrexia254222Vascular disorders Hemorrhage192+ 91 Hypertension 11552Infections and infestations Bronchitis132103 Skin infection 10362Metabolism and nutrition disorders Hyperuricemia10260The 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 and below 0.5%+ Includes events of hemorrhage with fatal outcome in the IMBRUVICA arm and event of neutropenia with 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 and atrial fibrillation was 3% in patients treated with IMBRUVICA BR and 1% in patients treated with placebo BR.iLLUMINATEAdverse reactions described below in Table 10 reflect exposure to IMBRUVICA obinutuzumab with median duration of 29.3 months and exposure to chlorambucil obinutuzumab with median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.Table 10: Adverse Reactions Reported in at Least 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATEBody SystemAdverse ReactionIMBRUVICA Obinutuzumab(N=113)Chlorambucil +Obinutuzumab(N=115)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)Blood and lymphatic system disorders Neutropenia48396448 Thrombocytopenia36192811 Anemia174258Skin and subcutaneous tissue disorders Rash363110 Bruising32330Gastrointestinal disorders Diarrhea343100 Constipation160121 Nausea120300Musculoskeletal and connective tissue disorders Musculoskeletal pain331233 Arthralgia221100 Muscle spasms13060Respiratory, thoracic and mediastinal disorders Cough271120Injury, poisoning and procedural complications Infusion related reaction252588Vascular disorders Hemorrhage25190 Hypertension17443General disorders and administration site conditions Pyrexia192261 Fatigue180172 Peripheral edema12070Infections and infestations Pneumonia16994+ Upper respiratory tract 14160 infection Skin infection13130 Urinary tract infection12371 Nasopharyngitis12030 Conjunctivitis11020Metabolism and nutrition disorders Hyperuricemia13100Cardiac disorders Atrial fibrillation12500Psychiatric disorders Insomnia12040The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms+ Includes one event with fatal outcome. E1912Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA rituximab with median duration of 34.3 months and exposure to FCR with median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger. Table 11: Adverse Reactions Reported in at Least 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912Body SystemAdverse ReactionIMBRUVICA Rituximab(N=352)Fludarabine Cyclophosphamide Rituximab(N=158)All Grades(%)Grade or Higher (%)All Grades(%)Grade or Higher (%)General disorders and administration site conditions Fatigue802783 Peripheral edema281170 Pyrexia271271 Pain23280Musculoskeletal and connective tissue disorders Musculoskeletal pain615352 Arthralgia415101Gastrointestinal disorders Diarrhea534271 Nausea401641 Stomatitis22181 Abdominal pain192101 Vomiting182280 Constipation170320Skin and subcutaneous tissue disorders Rash494295 Bruising36141Vascular disorders Hypertension4219226 Hemorrhage31281Nervous system disorders Headache401271 Dizziness211131 Peripheral neuropathy191131Respiratory, thoracic and mediastinal disorders Cough320250 Dyspnea222211Infections and infestations Upper respiratory tract 291192 infection Skin infection16131Metabolism and nutrition disorders Hyperuricemia19140 Decreased appetite150201Psychiatric disorders Insomnia161191The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR termsTable 12: 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 or 4(%)All Grades(%)Grade or 4(%)Hematology abnormalities Neutrophils decreased Platelets decreased Hemoglobin decreased534326307070695144252Chemistry abnormalities Creatinine increased Bilirubin increased AST increased38302512317152310<1Based on laboratory measurements per IWCLL criteriaWaldenstroms Macroglobulinemia and Marginal Zone LymphomaThe data described below reflect exposure to IMBRUVICA in three single-arm open-label clinical trials (Study 1118, Study 1121, and INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM or MZL, including total n=307 patients overall and n=232 patients exposed to IMBRUVICA. Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. Study 1121 included 63 patients with previously treated MZL who received single agent IMBRUVICA. INNOVATE included 150 patients with treatment naive 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 failed prior rituximab-containing therapy and received IMBRUVICA.The most common adverse reactions in Studies 1118, 1121, and INNOVATE (>= 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia, rash, fatigue, and nausea.Seven percent of patients receiving IMBRUVICA across Studies 1118, 1121, and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 13% of patients.Study 1118 and INNOVATE Monotherapy ArmAdverse reactions and laboratory abnormalities described below in Table 13 and Table 14 reflect exposure to IMBRUVICA with median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.Table 13: Non-Hematologic Adverse Reactions in >= 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)Gastrointestinal disordersDiarrheaNauseaStomatitisConstipationGastroesophageal reflux disease382115121220010Skin and subcutaneous tissue disordersBruisingRash282111Vascular disordersHemorrhageHypertension281404General disorders and administrative site conditionsFatiguePyrexia181222Musculoskeletal and connective tissue disordersMusculoskeletal painMuscle spasms211900Infections and infestationsUpper respiratory tract infectionSkin infectionSinusitisPneumonia191816130305Nervous system disordersHeadacheDizziness141300Respiratory, thoracic and mediastinal disordersCough130The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.Table 14: 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 or (%)Platelets Decreased3811Neutrophils Decreased4316Hemoglobin Decreased216Treatment-emergent Grade thrombocytopenia (4%) and neutropenia (7%) occurred in patients. INNOVATEAdverse reactions described below in Table 15 reflect exposure to IMBRUVICA R with median duration of 25.8 months and exposure to placebo R with median duration of 15.5 months in patients with treatment naive or previously treated WM in INNOVATE. Table 15: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with WM in INNOVATEBody SystemAdverse ReactionIMBRUVICA R(N=75)Placebo R(N=75)All Grades(%)Grade or Higher(%)All Grades(%)Grade or Higher(%)Skin and subcutaneous tissue disorders Bruising37150 Rash241110Musculoskeletal and connective tissue disorders Musculoskeletal pain354213 Arthralgia243111 Muscle spasms170121Vascular disorders Hemorrhage323174+ Hypertension201354Gastrointestinal disorders Diarrhea280151 Nausea210120 Dyspepsia16010 Constipation131111Infections and infestations Pneumonia191353 Skin infection17330 Urinary tract infection13000 Bronchitis12370 Influenza12071Viral upper respiratory tract infection11070General disorders and administration site conditions Peripheral edema170121Respiratory, thoracic, and mediastinal disorders Cough170110Blood and lymphatic system disorders Neutropenia1612114Cardiac disorders Atrial fibrillation151231Nervous system disorders Dizziness11070Psychiatric disorders Insomnia11040Metabolism and nutrition disorders Hypokalemia11011The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes one event with fatal outcome. Grade or infusion related reactions were observed in 1% of patients treated with IR.Study 1121Adverse reactions and laboratory abnormalities described below in Table 16 and Table 17 reflect exposure to IMBRUVICA with median duration of 11.6 months in Study 1121.Table 16: Non-Hematologic Adverse Reactions in >= 10% in Patients with MZL in Study 1121 (N=63)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)General disorders and administrative site conditionsFatiguePeripheral edemaPyrexia442417622Gastrointestinal disordersDiarrheaNauseaDyspepsiaStomatitisAbdominal painConstipationAbdominal pain upperVomiting432519171614131150022002Skin and subcutaneous tissue disordersBruising Rash Pruritus 412914050Musculoskeletal and connective tissue disordersMusculoskeletal painArthralgiaMuscle spasms402419323Infections and infestationsUpper respiratory tract infectionSinusitisBronchitisPneumonia2119111100010Metabolism and nutrition disordersDecreased appetiteHyperuricemiaHypoalbuminemiaHypokalemia161614132000Vascular disordersHemorrhageHypertension30142+ 5Respiratory, thoracic and mediastinal disordersCoughDyspnea222122Nervous system disordersDizzinessHeadache191300Psychiatric disordersAnxiety162The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes one event with fatal outcome.Table 17: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63)Percent of Patients (N=63)All Grades (%)Grade or (%)Platelets decreased496Hemoglobin decreased4313Neutrophils decreased2213Treatment-emergent Grade thrombocytopenia (3%) and neutropenia (6%) occurred in patients.Chronic Graft versus Host DiseaseThe 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.The most common adverse reactions in the cGVHD trial (>= 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 the cGVHD trial 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 median duration of 4.4 months in the cGVHD trial.Table 18: Non-Hematologic Adverse Reactions in >= 10% of Patients with cGVHD (N=42)Body SystemAdverse ReactionAll Grades (%)Grade or Higher (%)General disorders and administration site conditionsFatiguePyrexiaEdema peripheral5717121250Skin and subcutaneous tissue disordersBruisingRash401200Gastrointestinal disordersDiarrheaStomatitisNauseaConstipation3629261210200Musculoskeletal and connective tissue disordersMuscle spasmsMusculoskeletal pain291425Vascular disordersHemorrhage260Infections and infestationsPneumoniaUpper respiratory tract infectionSepsis21191014+ 010Nervous system disordersHeadache175Injury, poisoning and procedural complicationsFall170Respiratory, thoracic and mediastinal disordersCoughDyspnea141202Metabolism and nutrition disordersHypokalemia 12 The system organ class and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms.+ Includes events with fatal outcome. Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42)Percent of Patients (N=42)All Grades (%)Grade or (%)Platelets decreased330Neutrophils decreased1010Hemoglobin decreased242Treatment-emergent Grade neutropenia occurred in 2% of patients.Additional Important Adverse ReactionsCardiovascular EventsData 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 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 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 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 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively. DiarrheaIn 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 rate of 43% of patients treated with IMBRUVICA compared to 19% of patients in the control arm. Grade 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, to 708) versus 46 days (range, to 492) for any grade diarrhea and 117 days (range, to 414) versus 194 days (range, 11 to 325) for Grade 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 days (range, to 655) versus days (range, to 367) for any grade diarrhea and days (range, to 78) versus 19 days (range, to 56) for Grade diarrhea in IMBRUVICA-treated subjects compared to the control arm, respectively. Visual DisturbanceIn 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 or higher) compared to 6% in the control arm (5% Grade and <1% Grade and 3). Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, to 617) versus 100 days (range, 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, to 457) versus 26 days (range, to 721) in IMBRUVICA-treated subjects compared to the control arm, respectively. Long-Term SafetyThe safety data from long-term treatment with IMBRUVICA over years of 1,284 patients (treatment-naive CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) were analyzed. The median treatment duration was 51 months (range, 0.2 to 98 months) for CLL/SLL, 11 months (range, to 87 months) for MCL, and 47 months (range, 0.3 to 61 months) for WM. The cumulative rate of hypertension increased over time. The prevalence for Grade 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%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION Ibrutinib is an inhibitor of Brutons tyrosine kinase (BTK). It is white to off-white solid with the empirical formula C25H24N6O2 and molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:IMBRUVICA (ibrutinib) is available as immediate-release oral capsules and immediate-release oral tablets.IMBRUVICA (ibrutinib) capsules for oral use are available in the following dosage strengths: 70 mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg capsule only), and black ink.IMBRUVICA (ibrutinib) tablets for oral use are available in the following dosage strengths: 140 mg, 280 mg, 420 mg, and 560 mg. Each tablet contains ibrutinib (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).. Ibrutinib is an inhibitor of Brutons tyrosine kinase (BTK). It is white to off-white solid with the empirical formula C25H24N6O2 and molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION MCL and MZL: 560 mg taken orally once daily (2.1). CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.1).Dose should be taken orally with glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets (2.1).. MCL and MZL: 560 mg taken orally once daily (2.1). CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.1).. 2.1 Recommended Dosage. Mantle Cell Lymphoma and Marginal Zone LymphomaThe recommended dosage of IMBRUVICA for MCL and MZL is 560 mg orally once daily until disease progression or unacceptable toxicity.Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenstroms MacroglobulinemiaThe 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 single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR). For WM, IMBRUVICA can be administered as 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 DiseaseThe recommended dosage of IMBRUVICA for cGVHD is 420 mg orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical assessment of the individual patient.AdministrationAdminister IMBRUVICA at approximately the same time each day with glass of water. Swallow tablets or capsule whole. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets.If dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with 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. Interrupt IMBRUVICA therapy for any Grade or non-hematological toxicities, Grade or neutropenia with infection or fever, or Grade hematological toxicities. Once the adverse reaction has improved to Grade or baseline (recovery), IMBRUVICA may be reinitiated at the starting dose. If the adverse reaction reoccurs, reduce dose by 140 mg per day. Consider second reduction of dose by 140 mg as needed. If these adverse reactions persist or recur following two dose reductions, discontinue IMBRUVICA.Recommended dose modifications are described below:Toxicity OccurrenceDose Modification for MCL and MZL After RecoveryStarting Dose 560 mgDose Modification for CLL/SLL, WM, and cGVHD After RecoveryStarting Dose 420 mgFirstRestart at 560 mg dailyRestart at 420 mg dailySecondRestart at 420 mg dailyRestart at 280 mg dailyThirdRestart at 280 mg dailyRestart at 140 mg dailyFourthDiscontinue IMBRUVICADiscontinue IMBRUVICA. 2.3 Dosage Modifications for Use with CYP3A Inhibitors. Recommended dosage modifications are described below [see Drug Interactions 7.1 )]:Patient PopulationCoadministered DrugRecommended IMBRUVICA DosageB-Cell MalignanciesModerate CYP3A inhibitor280 mg once dailyModify 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 daily140 mg once dailyModify 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 daily70 mg once dailyInterrupt dose as recommended [see Dosage and Administration 2.2 )]. Other strong CYP3A inhibitorsAvoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA.Chronic Graft versus Host DiseaseModerate CYP3A inhibitor420 mg once dailyModify 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 daily280 mg once dailyModify 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 daily140 mg once dailyInterrupt dose as recommended [see Dosage and Administration 2.2 )]. Other strong CYP3A inhibitorsAvoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA.After discontinuation of CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage and Administration 2.1 ), Drug Interactions 7.1 )]. Moderate CYP3A inhibitor. Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. 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. Other strong CYP3A inhibitors. Moderate CYP3A inhibitor. Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. 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. Other strong CYP3A inhibitors. 2.4 Dosage Modifications for Use in Hepatic Impairment. 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 )].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Capsules:Each 70 mg capsule is yellow, opaque capsule marked with ibr 70 mg in black ink.Each 140 mg capsule is white, opaque capsule marked with ibr 140 mg in black ink.Tablets:Each 140 mg tablet is yellow green to green round tablet debossed with ibr on one side and 140 on the other side.Each 280 mg tablet is purple oblong tablet debossed with ibr on one side and 280 on the other side.Each 420 mg tablet is yellow green to green oblong tablet debossed with ibr on one side and 420 on the other side. Each 560 mg tablet is yellow to orange oblong tablet debossed with ibr on one side and 560 on the other side.. Capsules: 70 mg and 140 mg (3)Tablets: 140 mg, 280 mg, 420 mg, and 560 mg (3).

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1). CYP3A Inducers: Avoid coadministration with strong CYP3A inducers (7.2).. CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1). CYP3A Inducers: Avoid coadministration with strong CYP3A inducers (7.2).. 7.1 Effect of CYP3A Inhibitors on Ibrutinib. The coadministration of IMBRUVICA with strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations [see Clinical Pharmacology 12.3 )]. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA are recommended when used concomitantly with posaconazole, voriconazole and moderate CYP3A inhibitors [see Dosage and Administration 2.3 )]. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and Administration (2.3)].Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A.. 7.2 Effect of CYP3A Inducers on Ibrutinib. The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology 12.3 ].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were >= 65 years of age, while 23% were >=75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. 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 and B). Monitor patients more frequently for adverse reactions of IMBRUVICA [see Dosage and Administration 2.4 ), Clinical Pharmacology 12.3 )].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING CapsulesThe 70 mg capsules are supplied as yellow opaque capsules, marked with ibr 70 mg in black ink, in white HDPE bottles with child-resistant closure:28 capsules per bottle: NDC 57962-070-28The 140 mg capsules are supplied as white opaque capsules, marked with ibr 140 mg in black ink, in white HDPE bottles with child-resistant closure:90 capsules per bottle: NDC 57962-140-09 120 capsules per bottle: NDC 57962-140-12Store bottles at room temperature 20C to 25C (68F to 77F). Excursions are permitted between 15C and 30C (59F to 86F). Retain in original package until dispensing.TabletsThe IMBRUVICA (ibrutinib) tablets are supplied in strengths in the following packaging configurations: 140 mg tablets: Yellow green to green round tablets debossed with ibr on one side and 140 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-014-28 280 mg tablets: Purple oblong tablets debossed with ibr on one side and 280 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-280-28 420 mg tablets: Yellow green to green oblong tablets debossed with ibr on one side and 420 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-420-28 560 mg tablets: Yellow to orange oblong tablets debossed with ibr on one side and 560 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-560-28Store tablets in original packaging at room temperature 20C to 25C (68F to 77F). Excursions are permitted between 15C and 30C (59F to 86F).. 28 capsules per bottle: NDC 57962-070-28. 90 capsules per bottle: NDC 57962-140-09 120 capsules per bottle: NDC 57962-140-12. 140 mg tablets: Yellow green to green round tablets debossed with ibr on one side and 140 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-014-28 280 mg tablets: Purple oblong tablets debossed with ibr on one side and 280 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-280-28 420 mg tablets: Yellow green to green oblong tablets debossed with ibr on one side and 420 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-420-28 560 mg tablets: Yellow to orange oblong tablets debossed with ibr on one side and 560 on the other side. Carton of one folded blister card containing two 14-count blister strips for total of 28 tablets: NDC 57962-560-28.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE IMBRUVICA is kinase inhibitor indicated for the treatment of adult patients with:Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1).This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) (1.2). Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion (1.3). Waldenstroms macroglobulinemia (WM) (1.4). Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy (1.5).This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (1.6).. Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1).This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) (1.2). Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion (1.3). Waldenstroms macroglobulinemia (WM) (1.4). Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy (1.5).This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (1.6).. 1.1 Mantle Cell Lymphoma. IMBRUVICA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s) [see Clinical Studies 14.1 )].. 1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).. 1.3 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion. IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.. 1.4 Waldenstroms Macroglobulinemia. IMBRUVICA is indicated for the treatment of adult patients with Waldenstroms macroglobulinemia (WM).. 1.5 Marginal Zone Lymphoma. IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.This indication is approved under accelerated approval based on overall response rate [see Clinical Studies 14.4 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. 1.6 Chronic Graft versus Host Disease. IMBRUVICA is indicated for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Hemorrhage:Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, 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 (5.1)].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 (5.2)].Cardiac arrhythmias and cardiac failure:Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, chest discomfort, or edema [see Warning and Precautions 5.4 )] Hypertension:Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.5 )]. 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 (5.6)].Tumor lysis syndrome:Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].Embryo-fetal toxicity:Advise women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.8 ), Use in Specific Populations 8.1 )].Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose [see Use in Specific Populations 8.3 ].Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Lactation:Advise women not to breastfeed during treatment with IMBRUVICA and for week after the last dose [see Use in Specific Populations (8.2)].Inform patients to take IMBRUVICA orally once daily according to their physicians instructions and that the oral dosage (capsules or tablets) should be swallowed whole with glass of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets approximately the same time each day [see Dosage and Administration 2.1 )]. Advise patients that in the event of missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with return to the normal schedule the following day. Patients should not take extra doses to make up the missed dose [see Dosage and Administration 2.1 )]. Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions 6 )]. Direct the patient to 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 7 )]. 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 [see Adverse Reactions 6.1 )].Distributed and Marketed by:Pharmacyclics LLCSouth San Francisco, CA 94080 USAandMarketed by:Janssen Biotech, Inc.Horsham, PA 19044 USAPatent http://www.imbruvica.com IMBRUVICA(R) is registered trademark owned by Pharmacyclics LLC(C) Pharmacyclics LLC 2021(C) Janssen Biotech, Inc. 2021. Hemorrhage:Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, 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 (5.1)].. 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 (5.2)].. Cardiac arrhythmias and cardiac failure:Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, chest discomfort, or edema [see Warning and Precautions 5.4 )] . Hypertension:Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.5 )]. 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 (5.6)].. Tumor lysis syndrome:Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].. Embryo-fetal toxicity:Advise women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.8 ), Use in Specific Populations 8.1 )].Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose [see Use in Specific Populations 8.3 ].Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Lactation:Advise women not to breastfeed during treatment with IMBRUVICA and for week after the last dose [see Use in Specific Populations (8.2)].. Inform patients to take IMBRUVICA orally once daily according to their physicians instructions and that the oral dosage (capsules or tablets) should be swallowed whole with glass of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets approximately the same time each day [see Dosage and Administration 2.1 )]. Advise patients that in the event of missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with return to the normal schedule the following day. Patients should not take extra doses to make up the missed dose [see Dosage and Administration 2.1 )]. Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions 6 )]. Direct the patient to 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 7 )]. 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 [see Adverse Reactions 6.1 )].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ibrutinib is small-molecule inhibitor of BTK. Ibrutinib forms covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTKs 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ibrutinib was not carcinogenic in 6-month rasH2 mouse study at oral doses up to 2000 mg/kg/day resulting in exposures approximately 23 (males) to 37 (females) times higher than the exposure in humans at dose of 560 mg daily [see Warnings and Precautions 5.6 )].Ibrutinib was not mutagenic in bacterial mutagenicity (Ames) assay, was not clastogenic in chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.Rats were administered oral daily doses of ibrutinib for weeks prior to pairing and during pairing in males and weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).

OVERDOSAGE SECTION.

10 OVERDOSAGE There is no specific experience in the management of ibrutinib overdose in patients. One healthy subject experienced reversible Grade hepatic enzyme increases (AST and ALT) after dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.

PHARMACODYNAMICS SECTION.

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 vitro Platelet AggregationIbrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at 4.6 uM (2026 ng/mL), 0.8 uM (352 ng/mL), and uM (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 ElectrophysiologyAt single dose times the maximum recommended dose (1680 mg), IMBRUVICA did not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Ibrutinib exposure increases with doses up to 840 mg (1.5 times the maximum approved recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC (% coefficient of variation) observed in patients at 560 mg with MCL is 865 (69%) ngoh/mL and with MZL is 978 (82%) ngoh/mL, and in patients at 420 mg with CLL/SLL is 708 (71%) ngoh/mL, with WM is 707 (72%) ngoh/mL, and with cGVHD is 1159 (50%) ngoh/mL. Steady-state concentrations of ibrutinib without CYP3A inhibitors were achieved with an accumulation ratio of to 1.6 after week of multiple daily doses of 420 mg or 560 mg.AbsorptionAbsolute 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 median Tmax of hour to hours.Effect of FoodThe administration of IMBRUVICA with 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 Cmax 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 substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).DistributionReversible 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 (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10,000 L.EliminationIntravenous 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 hours to hours.MetabolismMetabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A and to minor extent by CYP2D6. The active metabolite, PCI-45227, is 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 to 2.8.ExcretionIbrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After 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 PopulationsAge and SexAge and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.Patients with Renal ImpairmentMild 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 ImpairmentThe 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 Cmax 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 )]. Drug Interaction StudiesClinical Studies and Model-Informed ApproachesEffect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole (strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady state Cmax 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 Cmax 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 Cmax 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 StudiesEffect 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 with narrow therapeutic index (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of IMBRUVICA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis Respiratory disorders: interstitial lung disease Metabolic and nutrition disorders: tumor lysis syndrome Immune system disorders: anaphylactic shock, angioedema, urticaria Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses Infections: hepatitis reactivation Nervous system disorders: peripheral neuropathy. Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis Respiratory disorders: interstitial lung disease Metabolic and nutrition disorders: tumor lysis syndrome Immune system disorders: anaphylactic shock, angioedema, urticaria Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses Infections: hepatitis reactivation Nervous system disorders: peripheral neuropathy.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryIMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform 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 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Data). Advise pregnant women of the potential risk to fetus.All pregnancies have 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.DataAnimal DataIbrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at 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 14 times the exposure (AUC) in patients with MCL or MZL and 20 times the exposure in patients with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. 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 times the exposure (AUC) in patients with MCL administered the dose of 560 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 dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at 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 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1)04/2020Warnings and Precautions (5.1, 5.2, 5.3, 5.5, 5.6)04/2020Warnings and Precautions (5.4) 12/2020.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONIMBRUVICA (im-BRU-vih-kuh)(ibrutinib)capsulesIMBRUVICA (im-BRU-vih-kuh)(ibrutinib)tabletsWhat is IMBRUVICAIMBRUVICA is prescription medicine used to treat adults with:Mantle cell lymphoma (MCL) who have received at least one prior treatment Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion Waldenstroms macroglobulinemia (WM) Marginal zone lymphoma (MZL) who require medicine by mouth or injection (systemic therapy) and have received certain type of prior treatment Chronic graft versus host disease (cGVHD) after failure of or more lines of systemic therapyIt is not known if IMBRUVICA is safe and effective in children.Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure. have bleeding problems have or had heart rhythm problems, smoke, or have medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes have an infection have liver problems are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do pregnancy test before starting treatment with IMBRUVICA. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA. Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA and for month after the last dose. Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA and for month after the last dose. are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects.How should take IMBRUVICATake IMBRUVICA exactly as your healthcare provider tells you to take it. Take IMBRUVICA time day. Swallow IMBRUVICA capsules or tablets whole with glass of water. Do not open, break, or chew IMBRUVICA capsules. Do not cut, crush, or chew IMBRUVICA tablets. Take IMBRUVICA at about the same time each day. If you miss dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take extra doses of IMBRUVICA to make up for missed dose. If you take too much IMBRUVICA call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking IMBRUVICAYou should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.What are the possible side effects of IMBRUVICAIMBRUVICA may cause serious side effects, including:Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including:blood in your stools or black stools (looks like tar) pink or brown urine unexpected bleeding, or bleeding that is severe or that you cannot control vomit blood or vomit looks like coffee grounds cough up blood or blood clotsincreased bruising dizziness weakness confusion change in your speech headache that lasts long time or severe headacheInfections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA.Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure and death have happened in people treated with IMBRUVICA, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles or legs, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do test to check your heart (ECG) and may change your IMBRUVICA dose. High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure. Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of the skin or other organs. Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.The most common side effects of IMBRUVICA in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:diarrhea tiredness muscle and bone painrash bruisingThe most common side effects of IMBRUVICA in adults with cGVHD include: tiredness bruising diarrheamouth sores (stomatitis) muscle spasms nauseapneumoniaDiarrhea is common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.These are not all the possible side effects of IMBRUVICA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IMBRUVICAStore IMBRUVICA capsules and tablets at room temperature between 68F to 77F (20C to 25C). Keep IMBRUVICA capsules in the original container with the lid tightly closed. Keep IMBRUVICA tablets in the original carton.Keep IMBRUVICA and all medicines out of the reach of children.General information about the safe and effective use of IMBRUVICA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use IMBRUVICA for condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals.What are the ingredients in IMBRUVICAActive ingredient: ibrutinib Inactive ingredients: IMBRUVICA capsules: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 70 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and black ink. The 140 mg capsule shell contains gelatin, titanium dioxide, and black ink. IMBRUVICA tablets: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).Distributed and Marketed by: Pharmacyclics LLC South San Francisco, CA 94080 USAMarketed by: Janssen Biotech, Inc. Horsham, PA 19044 USA.(C) Pharmacyclics LLC 2021(C) Janssen Biotech, Inc. 2021For more information, go to www.imbruvica.com or call 1-877-877-3536. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 10/2021. Mantle cell lymphoma (MCL) who have received at least one prior treatment Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion Waldenstroms macroglobulinemia (WM) Marginal zone lymphoma (MZL) who require medicine by mouth or injection (systemic therapy) and have received certain type of prior treatment Chronic graft versus host disease (cGVHD) after failure of or more lines of systemic therapy. have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure. have bleeding problems have or had heart rhythm problems, smoke, or have medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes have an infection have liver problems are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do pregnancy test before starting treatment with IMBRUVICA. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA. Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA and for month after the last dose. Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA and for month after the last dose. are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for week after the last dose. Take IMBRUVICA exactly as your healthcare provider tells you to take it. Take IMBRUVICA time day. Swallow IMBRUVICA capsules or tablets whole with glass of water. Do not open, break, or chew IMBRUVICA capsules. Do not cut, crush, or chew IMBRUVICA tablets. Take IMBRUVICA at about the same time each day. If you miss dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take extra doses of IMBRUVICA to make up for missed dose. If you take too much IMBRUVICA call your healthcare provider or go to the nearest hospital emergency room right away.. Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including:. blood in your stools or black stools (looks like tar) pink or brown urine unexpected bleeding, or bleeding that is severe or that you cannot control vomit blood or vomit looks like coffee grounds cough up blood or blood clots. increased bruising dizziness weakness confusion change in your speech headache that lasts long time or severe headache. Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA.. Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.. Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure and death have happened in people treated with IMBRUVICA, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles or legs, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do test to check your heart (ECG) and may change your IMBRUVICA dose. High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure. Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of the skin or other organs. Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.. diarrhea tiredness muscle and bone pain. rash bruising. tiredness bruising diarrhea. mouth sores (stomatitis) muscle spasms nausea. pneumonia. Store IMBRUVICA capsules and tablets at room temperature between 68F to 77F (20C to 25C). Keep IMBRUVICA capsules in the original container with the lid tightly closed. Keep IMBRUVICA tablets in the original carton.

SPL UNCLASSIFIED SECTION.

1.1 Mantle Cell Lymphoma. IMBRUVICA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s) [see Clinical Studies 14.1 )].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2)Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose (2.4, 8.6). Lactation: Advise not to breastfeed. (8.2). Hepatic Impairment (based on Child-Pugh criteria): 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 SummaryIMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform 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 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Data). Advise pregnant women of the potential risk to fetus.All pregnancies have 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.DataAnimal DataIbrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at 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 14 times the exposure (AUC) in patients with MCL or MZL and 20 times the exposure in patients with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. 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 times the exposure (AUC) in patients with MCL administered the dose of 560 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 dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at 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 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively.. 8.2 Lactation. Risk SummaryThere 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 week after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.ContraceptionFemalesIMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific Populations 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month following the last dose.. 8.4 Pediatric Use. The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. 8.5 Geriatric Use. Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were >= 65 years of age, while 23% were >=75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA.. 8.6 Hepatic Impairment. 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 and B). Monitor patients more frequently for adverse reactions of IMBRUVICA [see Dosage and Administration 2.4 ), Clinical Pharmacology 12.3 )]. 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.

WARNINGS AND PRECAUTIONS SECTION.

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).Cytopenias: Check complete blood counts monthly (5.3).Cardiac Arrhythmias and Cardiac Failure: Monitor for symptoms of arrhythmias and cardiac failure and manage (5.4). Hypertension: Monitor blood pressure and treat (5.5).Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.6).Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions. Monitor and treat for TLS (5.7).Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception (5.8, 8.1, 8.3).. Hemorrhage: Monitor for bleeding and manage (5.1).. Infections: Monitor patients for fever and infections, evaluate promptly, and treat (5.2).. Cytopenias: Check complete blood counts monthly (5.3).. Cardiac Arrhythmias and Cardiac Failure: Monitor for symptoms of arrhythmias and cardiac failure and manage (5.4). Hypertension: Monitor blood pressure and treat (5.5).. Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.6).. Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions. Monitor and treat for TLS (5.7).. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception (5.8, 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% 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.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 to 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 or greater infections occurred in 21% of 1,476 patients 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 Cytopenias. In 645 patients with B-cell malignancies who received IMBRUVICA as single agent, grade or neutropenia occurred in 23% of patients, grade or thrombocytopenia in 8% and grade or anemia in 3%, based on laboratory measurements.Monitor complete blood counts monthly.. 5.4 Cardiac Arrhythmias and Cardiac Failure. Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Grade or greater ventricular tachyarrhythmias occurred in 0.2% of patients, Grade or greater atrial fibrillation and atrial flutter occurred in 4%, and Grade or greater cardiac failure occurred in 1% of 1,476 patients who received IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and previous history of cardiac arrhythmias [see Adverse Reactions 6.1 )]. At baseline and then periodically, monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias and cardiac failure appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and Administration 2.2 )]. 5.5 Hypertension. Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months). Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.. 5.6 Second Primary Malignancies. Other malignancies (10%), including non-skin carcinomas (4%), occurred among the 1,476 patients who received IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).. 5.7 Tumor Lysis Syndrome. Tumor lysis syndrome has been infrequently reported with IMBRUVICA. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.. 5.8 Embryo-Fetal Toxicity. Based on findings in animals, IMBRUVICA can cause fetal harm when administered to 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 2-20 times higher than those reported in patients with hematologic malignancies. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for month after the last dose. [see Use in Specific Populations 8.1 )].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEIMBRUVICA (im-BRU-vih-kuh) (ibrutinib)Oral Suspension, for oral useThis Instructions for Use contains information about how to prepare and give dose of IMBRUVICA Oral Suspension.Read this Instructions for Use before you give IMBRUVICA to your child, and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your childs medical condition or treatment.Call your healthcare provider or 1-877-877-3536 if you need help or have any questions about how to give IMBRUVICA the right way.Important information you need to know before giving IMBRUVICA to your child.IMBRUVICA is for oral use only.Give IMBRUVICA exactly as your healthcare provider tells you to. If you miss giving dose it can be given as soon as possible on the same day. Do not give more than the prescribed dose in day. If your child takes too much IMBRUVICA call your healthcare provider for help.Keep these instructions for future use.Each IMBRUVICA carton contains (see Figure A):1 bottle of IMBRUVICA (called bottle in this Instructions for Use) with pre-inserted bottle adapter (called adapter in this Instructions for Use). Do not remove the bottle adapt r. reusable mL oral dosing syringes (called syringe in this Instructions for Use) measuring in 0.1 mL increments.Only use the syringes that come with IMBRUVICA. Do not use the syringes for other patients or with other medicines. If you cannot read the markings on the syringes, throw them away and call 1-877-877-3536 to get new ones.Preparing and giving dose of IMBRUVICAStep 1: Gather and check suppliesCheck your childs prescribed dose in milliliters (mLs). Find this mL marking on the syringe. If the dose is more than the marking on the syringe, split the dose between syringes as prescribed. Gather bottle and syringe(s) (see Figure ). Check the bottle and make sure that the bottle has IMBRUVICA Oral Suspension printed on it and the expiration date (EXP) has not passed. Figure ADo not use IMBRUVICA after the expiration date printed on the carton and the bottle after EXP.Do not use if the IMBRUVICA carton seal appears to be tampered with.Step 2: Record or check discard dateWhen opening the bottle for the first time, record the date that is 60 days from the day the bottle is opened underneath the words Discard Date (see Figure B). Use IMBRUVICA within 60 days after opening. Figure BDo not use IMBRUVICA past the discard date recorded on the bottle.Step 3: Shake bottle Shake well before each use (see Figure ).Figure CStep 4: Remove cap from bottlePress down and twist the cap counterclockwise to remove it from the bottle (see Figure D). If there is fluid on top of the adapter you may wipe it with clean disposable tissue.Do not remove the bottle adapter.Figure DStep 5: Attach syringe to bottleMake sure the syringe is clean and dry before use. Push the plunger down all the way. Gently insert tip of the syringe into the adapter. Turn the assembled bottle and syringe upside down (see Figure E).Figure EStep 6: Fill syringeSlowly pull the syringe plunger down, past the number of mLs for your prescribed dose (see Figure F). Check for air bubbles and proceed to Step for instructions on how to remove air bubbles. Figure FStep 7: Remove air bubbles and adjust to the prescribed dose (mL)Hold the syringe and tap the sides to send bubbles to the tip. With the syringe attached to the bottle, push the plunger up to remove the air bubbles from the top (see Figure G). After the bubbles are removed, push the plunger up until the top of the colored plunger is even with the markings on the syringe for the dose. Figure GAir bubbles must be removed to ensure the correct dose.Note: Repeat steps and if any air bubbles remain. Step 8: Remove syringe from bottleTurn the assembled bottle upright. Hold the middle of the syringe and carefully remove it from the bottle (see Figure H). Place the bottle aside.Figure HDo not touch the plunger of the syringe to avoid accidentally spilling the medicine before you are ready.Note: If more than syringe is needed to give the full dose, repeat steps to with the second syringe to complete the prescribed dose.Step 9: Give IMBRUVICAPlace the tip of the syringe along the inside of your childs cheek. Slowly push the plunger all the way in to give the entire dose (see Figure I). Repeat with second syringe if needed to complete the prescribed dose.Note: IMBRUVICA must be given as soon as possible after being drawn from the bottle. Note: Make sure your child drinks water after swallowing the dose of medicine. Figure IStep 10: Recap bottlePlace the cap back on the IMBRUVICA bottle (see Figure ). Make sure the bottle is tightly closed between each use.Figure JStep 11: Rinse syringeRemove plunger from the syringe, rinse only with water and air dry (see Figure K). Store the syringe in clean, dry place. Figure KDo not clean the syringe with soap or in the dishwasher.Turn over for more information How to store IMBRUVICA Oral SuspensionStore the bottle between 36F and 77F (2C and 25C). Do not freeze.Store IMBRUVICA and all medications out of sight and reach of children.How to dispose of IMBRUVICA Dispose of (throw away) any unused medicine within 60 days after first opening of the bottle. At the same time throw away any used or unused syringes.Ask your pharmacist how to properly dispose of the medicine. For syringe disposal, rinse and place in household trash. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Distributed and Marketed by:Pharmacyclics LLCSouth San Francisco, CA 94080 USAandMarketed by:Janssen Biotech, Inc.Horsham, PA 19044 USAPatent http://www.imbruvica.comIMBRUVICA(R) is registered trademark owned by Pharmacyclics LLC (C) 2022 Pharmacyclics LLC (C) 2022 Janssen Biotech, Inc. 20070481 R2Approved: 8/2022. IMBRUVICA is for oral use only.. Give IMBRUVICA exactly as your healthcare provider tells you to. If you miss giving dose it can be given as soon as possible on the same day. Do not give more than the prescribed dose in day. Keep these instructions for future use.. bottle of IMBRUVICA (called bottle in this Instructions for Use) with pre-inserted bottle adapter (called adapter in this Instructions for Use). Do not remove the bottle adapt r. 2 reusable mL oral dosing syringes (called syringe in this Instructions for Use) measuring in 0.1 mL increments.. Check your childs prescribed dose in milliliters (mLs). Find this mL marking on the syringe. If the dose is more than the marking on the syringe, split the dose between syringes as prescribed. Gather bottle and syringe(s) (see Figure ). Check the bottle and make sure that the bottle has IMBRUVICA Oral Suspension printed on it and the expiration date (EXP) has not passed. When opening the bottle for the first time, record the date that is 60 days from the day the bottle is opened underneath the words Discard Date (see Figure B). Use IMBRUVICA within 60 days after opening. Shake well before each use (see Figure ).. Press down and twist the cap counterclockwise to remove it from the bottle (see Figure D). If there is fluid on top of the adapter you may wipe it with clean disposable tissue.. Make sure the syringe is clean and dry before use. Push the plunger down all the way. Gently insert tip of the syringe into the adapter. Turn the assembled bottle and syringe upside down (see Figure E).. Slowly pull the syringe plunger down, past the number of mLs for your prescribed dose (see Figure F). Check for air bubbles and proceed to Step for instructions on how to remove air bubbles. Hold the syringe and tap the sides to send bubbles to the tip. With the syringe attached to the bottle, push the plunger up to remove the air bubbles from the top (see Figure G). After the bubbles are removed, push the plunger up until the top of the colored plunger is even with the markings on the syringe for the dose. Turn the assembled bottle upright. Hold the middle of the syringe and carefully remove it from the bottle (see Figure H). Place the bottle aside.. Place the tip of the syringe along the inside of your childs cheek. Slowly push the plunger all the way in to give the entire dose (see Figure I). Repeat with second syringe if needed to complete the prescribed dose.. Place the cap back on the IMBRUVICA bottle (see Figure ). Make sure the bottle is tightly closed between each use.. Remove plunger from the syringe, rinse only with water and air dry (see Figure K). Store the syringe in clean, dry place. Store the bottle between 36F and 77F (2C and 25C). Store IMBRUVICA and all medications out of sight and reach of children.. Ask your pharmacist how to properly dispose of the medicine. For syringe disposal, rinse and place in household trash. Warning. Figure A. Figure B. Figure C. Figure D. DiagramDescription automatically generated. DiagramDescription automatically generated. DiagramDescription automatically generated. Figure H. DiagramDescription automatically generated. picture containing vector graphicsDescription automatically generated. DiagramDescription automatically generated. Arrow.