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Imbruvica

Last reviewed on RxList: 4/30/2020
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 Professional Information

SIDE EFFECTS

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

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 (%) sGrade 3 or Higher (%)
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 8
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 11 0
Arthralgia 11 0
Respiratory, thoracic and mediastinal disorders Dyspnea 27 5
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
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 Decreased 57 17
Neutrophils Decreased 47 29
Hemoglobin Decreased 41 9
* Based on laboratory measurements and adverse reactions
Treatment-emergent Grade 4 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 Lymphoma

The data described below reflect exposure in one single-arm, open-label clinical trial (Study 1102) and four randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS, and iLLUMINATE) in patients with CLL/SLL (n=1,506 total and n=781 patients exposed to IMBRUVICA). Patients with creatinine clearance (CrCl) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN (upper limit of normal), or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 267 randomized patients with treatment naïve-CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil, HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab, and iLLUMINATE included 228 randomized patients with treatment naïve CLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab.

The most commonly occurring adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, bruising, nausea, fatigue, pyrexia, hemorrhage, and cough.

Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia. Adverse reactions leading to dose reduction occurred in approximately 7% 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 Higher (%)
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 malignancies 10 2
Vascular disorders Hypertension 16 8
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 Decreased 69 12
Neutrophils Decreased 53 26
Hemoglobin Decreased 43 0
* Based on laboratory measurements per IWCLL criteria and adverse reactions.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.

RESONATE

Adverse reactions and laboratory abnormalities described below in 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 Higher (%) All Grades (%) Grade 3 or Higher (%)
Gastrointestinal disorders
  Diarrhea 48 4 18 2
  Nausea 26 2 18 0
  Stomatitis* 17 1 6 1
  Constipation 15 0 9 0
  Vomiting 14 0 6 1
General disorders and administration site conditions
  Pyrexia 24 2 15 2
Infections and infestations
  Upper respiratory tract infection 16 1 11 2
  Pneumonia* 15 12 13 10
  Sinusitis* 11 1 6 0
  Urinary tract infection 10 4 5 1
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
Subjects with multiple events for a given adverse reaction (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
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 Decreased 51 23 57 26
Platelets Decreased 52 5 45 10
Hemoglobin Decreased 36 0 21 0
Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia (8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.

RESONATE-2

Adverse reactions 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 Higher (%) All Grades (%) Grade 3 or Higher (%)
Gastrointestinal disorders
  Diarrhea 42 4 17 0
  Stomatitis* 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
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

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 Higher (%) All Grades (%) Grade 3 or Higher (%)
Blood and lymphatic system disorders
  Neutropenia* 66 61 60 56
  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
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms
<1 used for frequency above 0 and below 0.5%
Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in the placebo + BR arm.

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

iLLUMINATE

Adverse reactions described below in Table 9 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 9: Adverse Reactions Reported in at Least 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE

Body System
Adverse Reaction§
IMBRUVICA + Obinutuzumab
(N=113)
Chlorambucil + Obinutuzumab
(N=115)
All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%)
Blood and lymphatic system disorders
  Neutropenia* 48 39 64 48
  Thrombocytopenia* 36 19 28 11
  Anemia 17 4 25 8
Skin and subcutaneous tissue disorders
  Rash* 36 3 11 0
  Bruising* 32 3 3 0
Gastrointestinal Disorders
  Diarrhea 34 3 10 0
  Constipation 16 0 12 1
  Nausea 12 0 30 0
Musculoskeletal and Connective Tissue Disorders
  Musculoskeletal Pain* 33 1 23 3
  Arthralgia 22 1 10 0
  Muscle spasms 13 0 6 0
Respiratory, Thoracic and Mediastinal Disorders
  Cough 27 1 12 0
Injury, Poisoning and Procedural Complications
  Infusion related reaction 25 2 58 8
Vascular disorders
  Hemorrhage* 25 1 9 0
  Hypertension* 17 4 4 3
Infections and Infestations
  Pneumonia* 16 9 9 4
  Upper Respiratory Tract Infection 14 1 6 0
  Skin infection* 13 1 3 0
  Urinary tract infection 12 3 7 1
  Nasopharyngitis 12 0 3 0
  Conjunctivitis 11 0 2 0
Metabolism and Nutrition Disorders
  Hyperuricemia 13 1 0 0
Cardiac Disorders
  Atrial Fibrillation 12 5 0 0
General Disorders and Administration Site Conditions
  Pyrexia 19 2 26 1
  Fatigue 18 0 17 2
  Peripheral edema 12 0 7 0
Psychiatric disorders
  Insomnia 12 0 4 0
§ The data are not an adequate basis for comparison of ADR rates between treatment arms.
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.

Waldenström’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 naïve or previously treated WM who received IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received IMBRUVICA.

The most commonly occurring 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 10 and 11 reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.

Table 10: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)

Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%)
Gastrointestinal disorders Diarrhea 38 2
Nausea 21 0
Stomatitis* 15 0
Constipation 12 1
Gastroesophageal reflux disease 12 0
Skin and subcutaneous tissue disorders Bruising* 28 1
Rash* 21 1
Vascular disorders Hemorrhage* 28 0
Hypertension* 14 4
General disorders and administrative site conditions Fatigue 18 2
Pyrexia 12 2
Musculoskeletal and connective tissue disorders Musculoskeletal pain* 21 0
Muscle spasms 19 0
Infections and infestations Upper respiratory tract infection 19 0
Skin infection* 18 3
Sinusitis* 16 0
Pneumonia* 13 5
Nervous system disorders Headache 14 0
Dizziness 13 0
Respiratory, thoracic and mediastinal disorders Cough 13 0
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.

Table 11: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)

  Percent of Patients (N=94)
All Grades (%) Grade 3 or 4 (%)
Platelets Decreased 38 11
Neutrophils Decreased 43 16
Hemoglobin Decreased 21 6
Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.

INNOVATE

Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.

Table 12: 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* 37 1 5 0
  Rash* 24 1 11 0
Musculoskeletal and connective tissue disorders
  Musculoskeletal pain* 35 4 21 3
  Arthralgia 24 3 11 1
  Muscle spasms 17 0 12 1
Vascular disorders
  Hemorrhage* 32 3 17 4
  Hypertension* 20 13 5 4
Gastrointestinal disorders
  Diarrhea 28 0 15 1
  Nausea 21 0 12 0
  Dyspepsia 16 0 1 0
  Constipation 13 1 11 1
Infections and infestations
  Pneumonia* 19 13 5 3
  Skin infection* 17 3 3 0
  Urinary tract infection 13 0 0 0
  Bronchitis 12 3 7 0
  Influenza 12 0 7 1
  Viral upper respiratory tract infection 11 0 7 0
General disorders and administration site conditions
  Peripheral edema 17 0 12 1
Respiratory, thoracic, and mediastinal disorders
  Cough 17 0 11 0
Blood and Lymphatic System Disorders
  Neutropenia* 16 12 11 4
Cardiac Disorders
  Atrial fibrillation 15 12 3 1
Nervous system disorders
  Dizziness 11 0 7 0
Psychiatric disorders
  Insomnia 11 0 4 0
Metabolism and nutrition disorders
  Hypokalemia 11 0 1 1
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Includes one event with a fatal outcome.

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

Study 1121

Adverse reactions and laboratory abnormalities described below in Tables 13 and 14 reflect exposure to IMBRUVICA with a median duration of 11.6 months in Study 1121.

Table 13: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with MZL in Study 1121 (N=63)

Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%)
Gastrointestinal disorders Diarrhea 43 5
Nausea 25 0
Dyspepsia 19 0
Stomatitis* 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 2
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
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 14: 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
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 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 15 and 16 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial.

Table 15: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with cGVHD (N=42)

Body System Adverse Reaction All Grades (%) Grade 3 or Higher (%)
General disorders and administration site conditions Fatigue 57 12
Pyrexia 17 5
Edema peripheral 12 0
Skin and subcutaneous tissue disorders Bruising* 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 14
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
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 16: 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
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 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 0.5% 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 9% versus 1.4% and for Grade 3 or greater was 4.1% versus 0.4% in patients treated with IMBRUVICA compared to patients in the control arm.

Diarrhea

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm), diarrhea of any grade occurred at a rate of 39% of patients treated with IMBRUVICA compared to 18% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. 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. Less than 1% of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.

Visual Disturbance

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (10% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (6% Grade 1 and <1% Grade 2 and 3). 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.

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 including acute and/or fatal events, hepatic cirrhosis
  • Respiratory disorders: interstitial lung disease
  • Metabolic and nutrition disorders: tumor lysis syndrome [see WARNINGS AND PRECAUTIONS]
  • Immune system disorders: anaphylactic shock, angioedema, urticaria
  • Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis
  • Infections: hepatitis B reactivation
  • Nervous system disorders: peripheral neuropathy

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

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