Imbruvica

Last updated on RxList: 1/13/2021
Imbruvica Side Effects Center

What Is Imbruvica?

Imbruvica (ibrutinib) is an inhibitor of Bruton's tyrosine kinase (BTK) used to treat patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

What Are Side Effects of Imbruvica?

Common side effects of Imbruvica include:

Dosage for Imbruvica

The recommended dose of Imbruvica for MCL is 560 mg (four 140 mg capsules) orally once daily.

What Drugs, Substances, or Supplements Interact with Imbruvica?

Imbruvica may interact with ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, grapefruit and oranges, carbamazepine, rifampin, phenytoin and St. John's Wort. Tell your doctor all medications and supplements you use.

Imbruvica During Pregnancy and Breastfeeding

Imbruvica is not recommended for use during pregnancy. It can harm a fetus. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Imbruvica (ibrutinib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Imbruvica Consumer Information

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Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using ibrutinib and call your doctor at once if you have:

  • severe or ongoing diarrhea;
  • chest pain, pounding heartbeats or fluttering in your chest, feeling like you might pass out;
  • severe headache, blurred vision, pounding in your neck or ears;
  • pale skin, cold hands and feet;
  • easy bruising or bleeding (nosebleeds, bleeding gums);
  • signs of bleeding inside your body--dizziness, confusion, problems with speech, prolonged headache, black or bloody stools, pink or brown urine, or coughing up blood or vomit that looks like coffee grounds;
  • signs of infection--fever, chills, weakness, mouth sores, cough with mucus, trouble breathing;
  • kidney problems--little or no urinating, swelling in your feet or ankles; or
  • signs of tumor cell breakdown--tiredness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth;

Common side effects may include:

  • diarrhea, nausea;
  • fever, cough, trouble breathing;
  • blisters or ulcers in your mouth;
  • feeling tired;
  • bruising, rash; or
  • muscle pain, bone pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Imbruvica (Ibrutinib Capsules)

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Imbruvica Professional Information

SIDE EFFECTS

The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:

  • Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Infections [see WARNINGS AND PRECAUTIONS]
  • Cytopenias [see WARNINGS AND PRECAUTIONS]
  • Cardiac Arrhythmias [see WARNINGS AND PRECAUTIONS]
  • Hypertension [see WARNINGS AND PRECAUTIONS]
  • Second Primary Malignancies [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]

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.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to IMBRUVICA in 6 trials as a single agent at 420 mg orally once daily in 475 patients and at 560 mg orally once daily in 174 patients and in 4 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 6 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 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 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 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 (ULN) 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 SystemAdverse ReactionAll Grades (%)Grade 3 or Higher (%)
Gastrointestinal disordersDiarrhea515
Nausea310
Constipation250
Abdominal pain245
Vomiting230
Stomatitis171
Dyspepsia110
General disorders and administration site conditionsFatigue415
Peripheral edema353
Pyrexia181
Asthenia143
Musculoskeletal and connective tissue disordersMusculoskeletal pain371
Muscle spasms140
Arthralgia110
Infections and infestationsUpper respiratory tract infection340
Urinary tract infection143
Pneumonia148*
Skin infections145
Sinusitis131
Skin and subcutaneous tissue disordersBruising300
Rash253
Petechiae110
Respiratory, thoracic and mediastinal disordersDyspnea275*
Cough190
Epistaxis110
Metabolism and nutrition disordersDecreased appetite212
Dehydration124
Nervous system disordersDizziness140
Headache130
* Includes one event with a fatal outcome.

Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with MCL (N=111)

Percent of Patients
(N=111)
All Grades (%)Grade 3 or 4 (%)
Platelets decreased5717
Neutrophils decreased4729
Hemoglobin decreased419
Treatment-emergent Grade 4 thrombocytopenia (6%) and neutropenia (13%) occurred in patients.
* Based on laboratory measurements and adverse reactions

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

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 to IMBRUVICA in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA).  In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab. RESONATE-2 included 267 randomized patients with treatment 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 1102

Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102

Body SystemAdverse ReactionAll Grades (%)Grade 3 or Higher (%)
Gastrointestinal disordersDiarrhea594
Constipation222
Nausea202
Stomatitis200
Vomiting182
Abdominal pain140
Dyspepsia120
Skin and subcutaneous tissue disordersBraising512
Rash250
Petechiae160
Infections and infestationsUpper respiratory tract infection472
Sinusitis226
Skin infection166
Pneumonia1210
Urinary tract infection122
General disorders and administration site conditionsFatigue336
Pyrexia242
Peripheral edema220
Asthenia146
Chills120
Musculoskeletal and connective tissue disordersMusculoskeletal pain256
Arthralgia240
Muscle spasms182
Respiratory, thoracic and mediastinal disordersCough220
Oropharyngeal pain140
Dyspnea120
Nervous system disordersDizziness200
Headache182
Vascular disordersHypertension168
Metabolism and nutrition disordersDecreased appetite162
Neoplasms 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 1102

Percent of Patients
(N=51)
All Grades (%)Grade 3 or 4 (%)
Platelets decreased6912
Neutrophils decreased5326
Hemoglobin decreased430
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.
* Based on laboratory measurements per IWCLL criteria and adverse reactions.

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 in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE

Body System Adverse ReactionIMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
Gastrointestinal disorders
Diarrhea484182
Nausea262180
Stomatitis*17161
Constipation15090
Vomiting14061
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*282181
Arthralgia17170
Muscle spasms13080
Skin and subcutaneous tissue disorders
Rash*243130
Petechiae14010
Braising*12010
General disorders and administration site conditions
Pyrexia242152t
Respiratory, thoracic and mediastinal disorders
Cough190231
Dyspnea122101
Infections and infestations
Upper respiratory tract infection161112t
Pneumonia*1512t13lot
Sinusitis*11160
Urinary tract infection10451
Nervous system disorders
Headache14160
Dizziness11050
Injury, poisoning and procedural complications
Contusion11030
Eye disorders
Vision blurred10030
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms
† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a fatal outcome in the ofatumumab arm.

Table 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 decreased51235726
Platelets decreased5254510
Hemoglobin decreased360210
Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia (8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.

RESONATE-2

Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 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 in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2

Body System Adverse ReactionIMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
Gastrointestinal disorders
Diarrhea424170
Nausea221391
Constipation161160
Stomatitis*14141
Vomiting130201
Abdominal pain*133111
Dyspepsia11020
Musculoskeletal and connective tissue disorders
Musculoskeletal pain364200
Arthralgia16171
Muscle spasms11050
General disorders and administration site conditions
Fatigue301385
Peripheral edema19190
Pyrexia170142
Respiratory, thoracic and mediastinal disorders
Cough220150
Dyspnea101100
Skin and subcutaneous tissue disorders
Rash*214122
Bruising*19070
Eye disorders
Dry eye17050
Lacrimation increased13060
Vision blurred13080
Visual acuity reduced11020
Infections and infestations
Upper respiratory tract infection172172
Skin infection*15231
Pneumonia*14874
Urinary tract infections10181
Vascular disorders
Hypertension*14410
Nervous system disorders
Headache121102
Dizziness110121
Investigations
Weight decreased100120
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms

Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE-2

IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Neutrophils Decreased55286731
Platelets Decreased4775814
Hemoglobin Decreased360392
Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia (11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients.

Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia (11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients.

HELIOS

Adverse reactions described below in Table 9 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 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 HELIOS

Body System Adverse ReactionIMBRUVICA + BR
(N=287)
Placebo + BR
(N=287)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
Blood and lymphatic system disorders
Neutropenia*66616056†
Thrombocytopenia*34162616
Gastrointestinal disorders
Diarrhea362231
Abdominal pain1218<1
Skin and subcutaneous tissue disorders
Rash *324251
Bruising*20<18<1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*292200
Muscle spasms12<150
General disorders and administration site conditions
Pyrexia254222
Vascular disorders
Hemorrhage*192t91
Hypertension*11552
Infections and infestations
Bronchitis132103
Skin infection*10362
Metabolism and nutrition disorders
Hyperuricemia10260
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%
*Includes multiple ADR terms
† Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in the placebo + BR arm.

Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR.

iLLUMINATE

Adverse reactions described below in Table 10 reflect exposure to IMBRUVICA + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.

Table 10: Adverse Reactions Reported in at Least 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in Illuminate

Body System Adverse ReactionIMBRUVICA + Obinutuzumab
(N=113)
Chlorambucil + Obinutuzumab
(N=115)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
Blood and lymphatic system disorders
Neutropenia*48396448
Thrombocytopenia*36192811
Anemia174258
Skin and subcutaneous tissue disorders
Rash*363110
Bruising*32330
Gastrointestinal disorders
Diarrhea343100
Constipation160121
Nausea120300
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*331233
Arthralgia221100
Muscle spasms13060
Respiratory, thoracic and mediastinal disorders
Cough271120
Injury, poisoning and procedural complications
Infusion related reaction252588
Vascular disorders
Hemorrhage*25190
Hypertension*17443
General disorders and administration site conditions
Pyrexia192261
Fatigue180172
Peripheral edema12070
Infections and infestations
Pneumonia*16994†
Upper respiratory tract infection14160
Skin infection*13130
Urinary tract infection12371
Nasopharyngitis12030
Conjunctivitis11020
Metabolism and nutrition disorders
Hyperuricemia13100
Cardiac disorders
Atrial fibrillation12500
Psychiatric disorders
Insomnia12040
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
*Includes multiple ADR terms
†Includes one event with a fatal outcome.

E1912

Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.

Table 11: Adverse Reactions Reported in at Least 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912

Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine + Cyclophosphamide + Rituximab
(N=158)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
General disorders and administration site conditions
Fatigue802783
Peripheral edema281170
Pyrexia271271
Pain23280
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*615352
Arthralgia415101
Gastrointestinal disorders
Diarrhea534271
Nausea401641
Stomatitis*22181
Abdominal pain*192101
Vomiting182280
Constipation170320
Skin and subcutaneous tissue disorders
Rash*494295
Bruising*36141
Vascular disorders
Hypertension*4219226
Hemorrhage*31281
Nervous system disorders
Headache401271
Dizziness211131
Peripheral neuropathy*191131
Respiratory, thoracic and mediastinal disorders
Cough320250
Dyspnea222211
Infections and infestations
Upper respiratory tract infection291192
Skin infection*16131
Metabolism and nutrition disorders
Hyperuricemia19140
Decreased appetite150201
Psychiatric disorders
Insomnia161191
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
*Includes multiple ADR terms

Table 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 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Hematology abnormalities
Neutrophils decreased53307044
Platelets decreased4376925
Hemoglobin decreased260512
Chemistry abnormalities
Creatinine increased381171
Bilirubin increased302150
AST increased25323<1

Based on laboratory measurements per IWCLL criteria

Waldenstrom's Macroglobulinemia And Marginal Zone Lymphoma

The 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 a 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 Arm

Adverse reactions and laboratory abnormalities described below in Tables 13 and 14 reflect exposure to IMBRUVICA with a 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 3 or Higher(%)
Gastrointestinal disordersDiarrhea382
Nausea210
Stomatitis*150
Constipation121
Gastroesophageal reflux disease120
Skin and subcutaneous tissue disordersBruising*281
Rash*211
Vascular disordersHemorrhage *280
Hypertension*144
General disorders and administrative siteFatigue182
conditionsPyrexia122
Musculoskeletal and connective tissue disordersMusculoskeletal pain *210
Muscle spasms190
Infections and infestationsUpper respiratory tract infection190
Skin infection*183
Sinusitis*160
Pneumonia*135
Nervous system disordersHeadache140
Dizziness130
Respiratory, thoracic and mediastinal disordersCough130
The 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)
AU Grades (%)Grade 3 or 4 (%)
Platelets Decreased3811
Neutrophils Decreased4316
Hemoglobin Decreased216
Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.

INNOVATE

Adverse reactions described below in Table 15 reflect exposure to IMBRUVICA + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment 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 INNOVATE

Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades (%)Grade 3 or Higher (%)All Grades (%)Grade 3 or Higher (%)
Skin and subcutaneous tissue disorders
Bruising*37150
Rash*241110
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*354213
Arthralgia243111
Muscle spasms170121
Vascular disorders
Hemorrhage*323174t
Hypertension*201354
Gastrointestinal disorders
Diarrhea280151
Nausea210120
Dyspepsia16010
Constipation131111
Infections and infestations
Pneumonia*191353
Skin infection*17330
Urinary tract infection13000
Bronchitis12370
Influenza12071
Viral upper respiratory tract infection11070
General disorders and administration site conditions
Peripheral edema170121
Respiratory, thoracic, and mediastinal disorders
Cough170110
Blood and lymphatic system disorders
Neutropenia*1612114
Cardiac disorders
Atrial fibrillation151231
Nervous system disorders
Dizziness11070
Psychiatric disorders
Insomnia11040
Metabolism and nutrition disorders
Hypokalemia11011
The body system and individual ADR preferred terms are sorted in descending frequency order.
*Includes multiple ADR terms.
†Includes one event with a fatal outcome.

Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR.

Study 1121

Adverse reactions and laboratory abnormalities described below in Tables 16 and 17 reflect exposure to IMBRUVICA with a 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 ReactionAU Grades (%)Grade 3 or Higher (%)
General disorders and administrative site conditionsFatigue446
Peripheral edema242
Pyrexia172
Gastrointestinal disordersDiarrhea435
Nausea250
Dyspepsia190
Stomatitis*172
Abdominal pain162
Constipation140
Abdominal pain upper130
Vomiting112
Skin and subcutaneous tissue disordersBruising*410
Rash*295
Pruritus140
Musculoskeletal and connective tissue disordersMusculoskeletal pain403
Arthralgia242
Muscle spasms193
Infections and infestationsUpper respiratory tract infection210
Sinusitis*190
Bronchitis110
Pneumonia*1110
Metabolism and nutrition disordersDecreased appetite162
Hyperuricemia160
Hypoalbuminemia140
Hypokalemia130
Vascular disordersHemorrhage*302†
Hypertension*145
Respiratory, thoracic and mediastinal disordersCough222
Dyspnea212
Nervous system disordersDizziness190
Headache130
Psychiatric disordersAnxiety162
The body system and individual ADR preferred terms are sorted in descending frequency order.
*Includes multiple ADR terms.
†Includes one event with a fatal outcome.

Table 17: 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 decreased496
Hemoglobin decreased4313
Neutrophils decreased2213
Treatment-emergent Grade 4 thrombocytopenia (3%) and neutropenia (6%) occurred in patients.

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 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 Tables 18 and 19 reflect exposure to IMBRUVICA with a 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 ReactionAU Grades (%)Grade 3 or Higher (%)
General disorders and administration site conditionsFatigue5712
Pyrexia175
Edema peripheral120
Skin and subcutaneous tissue disordersBruising*400
Rash*120
Gastrointestinal disordersDiarrhea3610
Stomatitis292
Nausea260
Constipation120
Musculoskeletal and connective tissue disordersMuscle spasms292
Musculoskeletal pain145
Vascular disordersHemorrhage260
Pneumonia2114t
Infections and infestationsUpper respiratory tract infection190
Sepsis1010
Nervous system disordersHeadache175
Injury, poisoning and procedural complicationsFall170
Respiratory, thoracic and mediastinal disordersCough140
Dyspnea122
Metabolism and nutrition disordersHypokalemia127
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
*Includes multiple ADR terms.
†Includes 2 events with a fatal outcome.

Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42)

Percent of Patients
(N=42)
AU Grades (%)Grade 3 or 4 (%)
Platelets decreased330
Neutrophils decreased1010
Hemoglobin decreased242
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.

Additional Important Adverse Reactions

Cardiovascular Events

Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with IMBRUVICA compared to patients in the control arm.

The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke, cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively.

Diarrhea

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.

Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus 89% had complete resolution, and 15% versus 11% had not reported resolution at time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control arm, respectively.

Visual Disturbance

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and <1% Grade 2 and 3).

Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had complete resolution and 40% versus 29% had not reported resolution at the time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IMBRUVICA-treated subjects compared to the control arm, respectively.

Long-Term Safety

The safety data from long-term follow-up over 5 years of 1,178 patients (treatment-naive CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated with IMBRUVICA were analyzed. The median treatment duration for CLL/SLL was 51 months (range, 0.2 to 98 months). The median treatment duration for MCL was 11 months (range, 0 to 87 months). The cumulative rate of hypertension increased over time with prolonged IMBRUVICA treatment. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.

Postmarketing Experience

The following adverse reactions have been identified during postapproval 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 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 B reactivation
  • Nervous system disorders: peripheral neuropathy

Read the entire FDA prescribing information for Imbruvica (Ibrutinib Capsules)

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