Data from FDA - Curated by EPG Health - Last updated 31 August 2018

Indication(s)

1 INDICATIONS AND USAGE IMBRUVICA is a kinase inhibitor indicated for the treatment of adult patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1). Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) (1.2). Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion (1.3). Waldenström's 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). Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 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. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial [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 Waldenström's Macroglobulinemia IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s 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. Accelerated approval was granted for this indication 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 a confirmatory trial. 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS None None (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of 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 [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 adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, hemorrhage, and pyrexia (6). The most common adverse reactions (≥20%) in patients with cGVHD were 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring 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 Tables 1 and 2). The most common Grade 3 or 4 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 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 51 5 Nausea 31 0 Constipation 25 0 Abdominal pain 24 5 Vomiting 23 0 Stomatitis 17 1 Dyspepsia 11 0 Infections and infestations Upper respiratory tract infection 34 0 Urinary tract infection 14 3 Pneumonia 14 7 Skin infections 14 5 Sinusitis 13 1 General disorders and administration site conditions Fatigue 41 5 Peripheral edema 35 3 Pyrexia 18 1 Asthenia 14 3 Skin and subcutaneous tissue disorders Bruising 30 0 Rash 25 3 Petechiae 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 37 1 Muscle spasms 14 0 Arthralgia 11 0 Respiratory, thoracic and mediastinal disorders Dyspnea 27 4 Cough 19 0 Epistaxis 11 0 Metabolism and nutrition disorders Decreased appetite 21 2 Dehydration 12 4 Nervous system disorders Dizziness 14 0 Headache 13 0 Table 2: Treatment-EmergentBased on laboratory measurements and adverse reactions Hematologic Laboratory Abnormalities in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 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 Lymphoma The data described below reflect exposure in one single-arm, open-label clinical trial (Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to IMBRUVICA). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil, and HELIOS included 578 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab. The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and HELIOS in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1102, RESONATE, RESONATE-2, and HELIOS discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients. Study 1102 Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102 Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 59 4 Constipation 22 2 Nausea 20 2 Stomatitis 20 0 Vomiting 18 2 Abdominal pain 14 0 Dyspepsia 12 0 Infections and infestations Upper respiratory tract infection 47 2 Sinusitis 22 6 Skin infection 16 6 Pneumonia 12 10 Urinary tract infection 12 2 General disorders and administration site conditions Fatigue 33 6 Pyrexia 24 2 Peripheral edema 22 0 Asthenia 14 6 Chills 12 0 Skin and subcutaneous tissue disorders Bruising 51 2 Rash 25 0 Petechiae 16 0 Respiratory, thoracic and mediastinal disorders Cough 22 0 Oropharyngeal pain 14 0 Dyspnea 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 25 6 Arthralgia 24 0 Muscle spasms 18 2 Nervous system disorders Dizziness 20 0 Headache 18 2 Metabolism and nutrition disorders Decreased appetite 16 2 Neoplasms benign, malignant, unspecified Second malignanciesOne patient death due to histiocytic sarcoma. 12 0 Vascular disorders Hypertension 16 8 Table 4: Treatment-EmergentBased on laboratory measurements per IWCLL criteria and adverse reactions. Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102 Percent of Patients (N=51) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 69 12 Neutrophils Decreased 53 26 Hemoglobin Decreased 43 0 RESONATE Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL. Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE Body System Adverse Reaction IMBRUVICA (N=195) Ofatumumab (N=191) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Gastrointestinal disorders Diarrhea 48 4 18 2 Nausea 26 2 18 0 StomatitisIncludes multiple ADR terms 17 1 6 1 Constipation 15 0 9 0 Vomiting 14 0 6 1 General disorders and administration site conditions Pyrexia 24 2 15 1 Infections and infestations Upper respiratory tract infection 16 1 11 2 Pneumonia 15 10 13 9 Sinusitis 11 1 6 0 Urinary tract infection 10 4 5 1 Skin and subcutaneous tissue disorders Rash 24 3 13 0 Petechiae 14 0 1 0 Bruising 12 0 1 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 28 2 18 1 Arthralgia 17 1 7 0 Nervous system disorders Headache 14 1 6 0 Dizziness 11 0 5 0 Injury, poisoning and procedural complications Contusion 11 0 3 0 Eye disorders Vision blurred 10 0 3 0 Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE IMBRUVICA (N=195) Ofatumumab (N=191) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Neutrophils Decreased 51 23 57 26 Platelets Decreased 52 5 45 10 Hemoglobin Decreased 36 0 21 0 RESONATE-2 Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2. Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2 Body System Adverse Reaction IMBRUVICA (N=135) Chlorambucil (N=132) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Gastrointestinal disorders Diarrhea 42 4 17 0 StomatitisIncludes multiple ADR terms 14 1 4 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 36 4 20 0 Arthralgia 16 1 7 1 Muscle spasms 11 0 5 0 Eye disorders Dry eye 17 0 5 0 Lacrimation increased 13 0 6 0 Vision blurred 13 0 8 0 Visual acuity reduced 11 0 2 0 Skin and subcutaneous tissue disorders Rash 21 4 12 2 Bruising 19 0 7 0 Infections and infestations Skin infection 15 2 3 1 Pneumonia 14 8 7 4 Urinary tract infections 10 1 8 1 Respiratory, thoracic and mediastinal disorders Cough 22 0 15 0 General disorders and administration site conditions Peripheral edema 19 1 9 0 Pyrexia 17 0 14 2 Vascular disorders Hypertension 14 4 1 0 Nervous system disorders Headache 12 1 10 2 HELIOS Adverse reactions described below in Table 8 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL. Table 8: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS Body System Adverse Reaction Ibrutinib + BR (N=287) Placebo + BR (N=287) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. <1 used for frequency above 0 and below 0.5% Blood and lymphatic system disorders NeutropeniaIncludes multiple ADR terms 66 61 60 55 Thrombocytopenia 34 16 26 16 Skin and subcutaneous tissue disorders Rash 32 4 25 1 Bruising 20 <1 8 <1 Gastrointestinal disorders Diarrhea 36 2 23 1 Abdominal pain 12 1 8 <1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 29 2 20 0 Muscle spasms 12 <1 5 0 General disorders and administration site conditions Pyrexia 25 4 22 2 Vascular disorders Hemorrhage 19 2 9 1 Hypertension 11 5 5 2 Infections and infestations Bronchitis 13 2 10 3 Skin infection 10 3 6 2 Metabolism and nutrition disorders Hyperuricemia 10 2 6 0 Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo +BR. Waldenström's Macroglobulinemia and Marginal Zone Lymphoma The data described below reflect exposure to IMBRUVICA in open-label clinical trials that included 63 patients with previously treated WM (Study 1118) and 63 patients with previously treated MZL (Study 1121). The most commonly occurring adverse reactions in Studies 1118 and 1121 (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, fatigue, bruising, hemorrhage, anemia, rash, musculoskeletal pain, and nausea. Nine percent of patients receiving IMBRUVICA across Studies 1118 and 1121 discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 10% of patients. Study 1118 Adverse reactions and laboratory abnormalities described below in Tables 9 and 10 reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118. Table 9: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 (N=63) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) The body system and individual ADR preferred terms are sorted in descending frequency order. Gastrointestinal disorders Diarrhea 37 0 Nausea 21 0 StomatitisIncludes multiple ADR terms. 16 0 Gastroesophageal reflux disease 13 0 Skin and subcutaneous tissue disorders Rash 22 0 Bruising 16 0 Pruritus 11 0 General disorders and administrative site conditions Fatigue 21 0 Musculoskeletal and connective tissue disorders Muscle spasms 21 0 Arthropathy 13 0 Infections and infestations Upper respiratory tract infection 19 0 Sinusitis 19 0 Pneumonia 14 6 Skin infection 14 2 Respiratory, thoracic and mediastinal disorders Epistaxis 19 0 Cough 13 0 Nervous system disorders Dizziness 14 0 Headache 13 0 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin cancer 11 0 Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 (N=63) Percent of Patients (N=63) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 43 13 Neutrophils Decreased 44 19 Hemoglobin Decreased 13 8 Study 1121 Adverse reactions and laboratory abnormalities described below in Tables 11 and 12 reflect exposure to IMBRUVICA with a median duration of 11.6 months in Study 1121. Table 11: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with MZL in Study 1121 (N=63) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) The body system and individual ADR preferred terms are sorted in descending frequency order. Gastrointestinal disorders Diarrhea 43 5 Nausea 25 0 Dyspepsia 19 0 StomatitisIncludes multiple ADR terms. 17 2 Abdominal pain 16 2 Constipation 14 0 Abdominal pain upper 13 0 Vomiting 11 2 General disorders and administrative site conditions Fatigue 44 6 Peripheral edema 24 2 Pyrexia 17 2 Skin and subcutaneous tissue disorders Bruising 41 0 Rash 29 5 Pruritus 14 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 40 3 Arthralgia 24 2 Muscle spasms 19 3 Infections and infestations Upper respiratory tract infection 21 0 Sinusitis 19 0 Bronchitis 11 0 Pneumonia 11 10 Metabolism and nutrition disorders Decreased appetite 16 2 Hyperuricemia 16 0 Hypoalbuminemia 14 0 Hypokalemia 13 0 Vascular disorders Hemorrhage 30 0 Hypertension 14 5 Respiratory, thoracic and mediastinal disorders Cough 22 2 Dyspnea 21 2 Nervous system disorders Dizziness 19 0 Headache 13 0 Psychiatric disorders Anxiety 16 2 Table 12: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63) Percent of Patients (N=63) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 49 6 Hemoglobin Decreased 43 13 Neutrophils Decreased 22 13 Chronic Graft versus Host Disease The data described below reflect exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy. The most commonly occurring 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 Tables 13 and 14 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial. Table 13: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with cGVHD (N=42) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) The system organ class and individual ADR preferred terms are sorted in descending frequency order. General disorders and administration site conditions Fatigue 57 12 Pyrexia 17 5 Edema peripheral 12 0 Skin and subcutaneous tissue disorders BruisingIncludes multiple ADR terms. 40 0 Rash 12 0 Gastrointestinal disorders Diarrhea 36 10 Stomatitis 29 2 Nausea 26 0 Constipation 12 0 Musculoskeletal and connective tissue disorders Muscle spasms 29 2 Musculoskeletal pain 14 5 Vascular disorders Hemorrhage 26 0 Infections and infestations Pneumonia 21 10 Upper respiratory tract infection 19 0 Sepsis 10 10 Nervous system disorders Headache 17 5 Injury, poisoning and procedural complications Fall 17 0 Respiratory, thoracic and mediastinal disorders Cough 14 0 Dyspnea 12 2 Metabolism and nutrition disorders Hypokalemia 12 7 Table 14: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42) Percent of Patients (N=42) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 33 0 Neutrophils Decreased 10 10 Hemoglobin Decreased 24 2 Additional Important Adverse Reactions Cardiac Arrhythmias In randomized controlled trials (n=1227; median treatment duration of 13.1 months for patients treated with IMBRUVICA and 9.0 months for 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 0.2% and of Grade 3 or greater was 0.2% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 7% versus 1.5% and for Grade 3 or greater was 2.8% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm. Diarrhea Diarrhea of any grade occurred at a rate of 43% (range, 36% to 59%) of patients treated with IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 14%) and Grade 3 in 3% (range, 0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade diarrhea was 10 days (range, 0 to 627), of Grade 2 was 39 days (range, 1 to 719) and of Grade 3 was 74 days (range, 3 to 627). Of the patients who reported diarrhea, 82% had complete resolution, 1% had partial improvement and 17% had no reported improvement at time of analysis. The median time from onset to resolution or improvement of any grade diarrhea was 5 days (range, 1 to 418), and was similar for Grades 2 and 3. Less than 1% of patients discontinued IMBRUVICA due to diarrhea. Visual Disturbance Blurred vision and decreased visual acuity of any grade occurred in 10% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2). The median time to first onset was 85 days (range, 1 to 414 days). Of the patients with visual disturbance, 61% had complete resolution and 38% had no reported improvement at time of analysis. The median time from onset to resolution or improvement was 29 days (range, 1 to 335 days). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary disorders: hepatic failure Respiratory disorders: interstitial lung disease Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions (5.7)] Immune system disorders: anaphylactic shock, angioedema, urticaria Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis Infections: hepatitis B reactivation

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION MCL and MZL: 560 mg taken orally once daily (2.2). CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.2). Dose should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets (2.1). 2.1 Dosing Guidelines Administer IMBRUVICA orally once daily at approximately the same time each day. The dose should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. 2.2 Recommended Dosage Mantle Cell Lymphoma and Marginal Zone Lymphoma The recommended dose 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 Waldenström's Macroglobulinemia The recommended dose of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily until disease progression or unacceptable toxicity. The recommended dose of IMBRUVICA for CLL/SLL when used in combination with bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg orally once daily until disease progression or unacceptable toxicity. Chronic Graft versus Host Disease The recommended dose of IMBRUVICA for cGVHD is 420 mg orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical assessment of the individual patient. 2.3 Dose Modifications for Adverse Reactions Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by 140 mg per day. A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue IMBRUVICA. Recommended dose modifications are described below: Toxicity Occurrence Dose Modification for MCL and MZL After Recovery Starting Dose = 560 mg Dose Modification for CLL/SLL, WM, and cGVHD After Recovery Starting Dose = 420 mg First Restart at 560 mg daily Restart at 420 mg daily Second Restart at 420 mg daily Restart at 280 mg daily Third Restart at 280 mg daily Restart at 140 mg daily Fourth Discontinue IMBRUVICA Discontinue IMBRUVICA 2.4 Dose Modifications for Use with CYP3A Inhibitors Recommended dose modifications are described below [see Drug Interactions (7.1)] : Patient Population Coadministered Drug Recommended IMBRUVICA Dose B-Cell Malignancies Moderate CYP3A inhibitor Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 140 mg once daily Interrupt dose as recommended [see Dosage and Administration (2.3)]. Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole IV injection 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 70 mg once daily Interrupt dose as recommended [see Dosage and Administration (2.3). Other strong CYP3A inhibitors Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. Chronic Graft versus Host Disease Moderate CYP3A inhibitor 420 mg once daily Modify dose as recommended [see Dosage and Administration (2.3)]. Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 280 mg once daily Modify dose as recommended [see Dosage and Administration (2.3)]. Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole IV injection 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 140 mg once daily Interrupt dose as recommended [see Dosage and Administration (2.3). Other strong CYP3A inhibitors Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage and Administration (2.2) and Drug Interactions (7.1)]. 2.5 Dose Modifications for Use in Hepatic Impairment The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A). The recommended dose 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) and Clinical Pharmacology (12.3)]. 2.6 Missed Dose If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra doses of IMBRUVICA should not be taken to make up for the missed dose.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose (2.5, 8.6). 8.1 Pregnancy Risk Summary IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Animal Data). If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 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 6 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 a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.0 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 Summary There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for IMBRUVICA and any potential adverse effects on the breastfed child from IMBRUVICA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating IMBRUVICA therapy. Contraception Females Advise females of reproductive potential to avoid pregnancy while taking IMBRUVICA and for up to 1 month after ending treatment. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus. Males Advise men to avoid fathering a child while receiving IMBRUVICA, and for 1 month following the last dose of IMBRUVICA. 8.4 Pediatric Use The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. 8.5 Geriatric Use Of the 905 patients in clinical studies of IMBRUVICA, 62% were ≥ 65 years of age, while 21% were ≥75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades) and Grade 3 or higher pneumonia 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. Dose modifications of IMBRUVICA are recommended in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients for adverse reactions of IMBRUVICA closely [see Dosage and Administration (2.5) and 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.

Interactions

7 DRUG INTERACTIONS CYP3A Inhibitors: Dose adjustments may be recommended (2.4, 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 a 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 (2.4)]. 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 (2.4)]. 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)]. Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wortb.

More information

Category Value
Authorisation number NDA210563
Agency product number 1X70OSD4VX
Orphan designation No
Product NDC 57962-014,57962-280,57962-070,57962-140,57962-560,57962-420
Date Last Revised 07-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1442992
Storage and handling Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package until dispensing. The IMBRUVICA (ibrutinib) tablets are supplied in 4 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 a 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 a 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 a 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 a total of 28 tablets: NDC 57962-560-28 Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F).
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