Imbruvica Drug Information
Generic name: IBRUTINIB
Kinase Inhibitor [EPC]
Uses of Imbruvica
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. 2 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. 3 Waldenström’s Macroglobulinemia IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM). 1. 4 Chronic Graft versus Host Disease IMBRUVICA is indicated for the treatment of adult and pediatric patients age 1 year and older with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.
Dosage & Administration of Imbruvica
Recommended Dosage Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s Macroglobulinemia The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily until disease progression or unacceptable toxicity. For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR). When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is 420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240 mg/m 2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical assessment of the individual patient. Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than 12 years of age using either IMBRUVICA capsules/tablets or oral suspension *BSA = body surface area.
Administration Administer IMBRUVICA at approximately the same time each day. Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the capsules.
Do not cut, crush, or chew the tablets. Follow Instructions for Use for further administration details of IMBRUVICA oral suspension. If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day.
Do not take extra doses of IMBRUVICA to make up for the missed dose.
Dosage Modifications for Adverse Reactions
For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage modifications (see Table 2 ). Table 2: Recommended Dosage Modifications for Adverse Reactions a. b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL. c Evaluate the benefit-risk before resuming treatment. d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA capsules/tablets or oral suspension *BSA = body surface area.
Dosage Modifications for Use with CYP3A Inhibitors
- Recommended dosage modifications are described below: Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors once daily Modify dose as recommended. Other strong CYP3A inhibitors Avoid concomitant use. Patients 12 years and older with cGVHD Moderate CYP3A inhibitor 420 mg once daily Modify dose as recommended. After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA.
Dosage Modifications for Use in Hepatic Impairment Adult Patients with B-cell Malignancies The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A). The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-Pugh class B). Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C).
Patients with cGVHD The recommended dosage is 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
| Recommended dose to achieve 240 mg/m 2 | ||
| BSA* (m 2 ) Range | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer |
| > 0.3 to 0.4 | - | 1.2 mL |
| > 0.4 to 0.5 | - | 1.5 mL |
| > 0.5 to 0.6 | - | 1.9 mL |
| > 0.6 to 0.7 | - | 2.2 mL |
| > 0.7 to 0.8 | 210 mg | 2.6 mL |
| > 0.8 to 0.9 | 210 mg | 2.9 mL |
| > 0.9 to 1 | 210 mg | 3.3 mL |
| > 1 to 1.1 | 280 mg | 3.6 mL |
| > 1.1 to 1.2 | 280 mg | 4 mL |
| > 1.2 to 1.3 | 280 mg | 4.3 mL |
| > 1.3 to 1.4 | 350 mg | 4.6 mL |
| > 1.4 to 1.5 | 350 mg | 5 mL |
| > 1.5 to 1.6 | 350 mg | 5.3 mL |
| > 1.6 | 420 mg | 6 mL |
| Adverse Reaction a,b | Occurrence | Dose Modification for CLL/SLL, WM, and Patients 12 Years or older with cGVHD After Recovery Starting Dose = 420 mg | Dose Modification for Patients 1 Year to less than 12 Years with cGVHD After Recovery Starting Dose = 240 mg/m 2 |
|---|---|---|---|
| Grade 2 cardiac failure | First | Restart at 280 mg daily c | Restart at 160 mg/m 2 daily c |
| Second | Restart at 140 mg daily c | Restart at 80 mg/m 2 daily c | |
| Third | Discontinue IMBRUVICA | Discontinue IMBRUVICA | |
| Grade 3 cardiac arrhythmias | First | Restart at 280 mg daily c | Restart at 160 mg/m 2 daily c |
| Second | Discontinue IMBRUVICA | Discontinue IMBRUVICA | |
| Grade 3 or 4 cardiac failure Grade 4 cardiac arrhythmias | First | Discontinue IMBRUVICA | Discontinue IMBRUVICA |
| Other Grade 3 or 4 non-hematological toxicities d Grade 3 or 4 neutropenia with infection or fever Grade 4 hematological toxicities | First | Restart at 280 mg daily | Restart at 160 mg/m 2 daily c |
| Second | Restart at 140 mg daily | Restart at 80 mg/m 2 daily c | |
| Third | Discontinue IMBRUVICA | Discontinue IMBRUVICA |
| Recommended dose to achieve 160 mg/m 2 | Recommended dose to achieve 80 mg/m 2 | |||
|---|---|---|---|---|
| BSA* (m 2 ) Range | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer |
| > 0.3 to 0.4 | - | 0.8 mL | - | 0.4 mL |
| > 0.4 to 0.5 | - | 1 mL | - | 0.5 mL |
| > 0.5 to 0.6 | - | 1.3 mL | - | 0.6 mL |
| > 0.6 to 0.7 | - | 1.5 mL | - | 0.7 mL |
| > 0.7 to 0.8 | 140 mg | 1.7 mL | 70 mg | 0.9 mL |
| > 0.8 to 0.9 | 140 mg | 1.9 mL | 70 mg | 1 mL |
| > 0.9 to 1 | 140 mg | 2.2 mL | 70 mg | 1.1 mL |
| > 1 to 1.1 | 140 mg | 2.4 mL | 70 mg | 1.2 mL |
| > 1.1 to 1.2 | 210 mg | 2.6 mL | - | 1.3 mL |
| > 1.2 to 1.3 | 210 mg | 2.9 mL | - | 1.4 mL |
| > 1.3 to 1.4 | 210 mg | 3.1 mL | - | 1.5 mL |
| > 1.4 to 1.5 | 210 mg | 3.3 mL | 140 mg | 1.7 mL |
| > 1.5 to 1.6 | 280 mg | 3.5 mL | 140 mg | 1.8 mL |
| > 1.6 | 280 mg | 4 mL | 140 mg | 2 mL |
| Patient Population | Coadministered Drug | Recommended IMBRUVICA Dosage |
|---|---|---|
| B-cell Malignancies | Moderate CYP3A inhibitor | 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. |
| Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 140 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. | |
| Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 70 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2 )]. | |
| Other strong CYP3A inhibitors | Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. | |
| Patients 12 years and older with cGVHD | Moderate CYP3A inhibitor | 420 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. |
| Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. | |
| Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 140 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2 )]. | |
| Other strong CYP3A inhibitors | Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. | |
| Patients 1 year to less than 12 years of age with cGVHD | Moderate CYP3A inhibitors | 240 mg/m 2 once daily Modify dose as recommended [see Dosage and Administration ( 2.2 )]. |
| Voriconazole for suspension 9 mg/kg (maximum dose: 350 mg) twice daily | 160 mg/m 2 once daily | |
| Posaconazole at any dosage | 80 mg/m 2 once daily | |
| Other strong CYP3A inhibitors | Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. |
Side Effects of Imbruvica
Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily, and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies.
The most common adverse reactions (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma The data described below reflect exposure to IMBRUVICA in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA).
In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL.
RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab. RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab.
E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR). 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. Table 5: Non-Hematologic One patient death due to histiocytic sarcoma. Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL N= 0 Based on laboratory measurements per IWCLL criteria and adverse reactions.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients. RESONATE Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL. RESONATE-2 Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect exposure to IMBRUVICA with a median duration of 17.4 months.
The median exposure to chlorambucil was 7.1 months in RESONATE-2. Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2 0 Subjects with multiple events for a given ADR term are counted once only for each ADR term. HELIOS Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL.
Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS 6 0 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms. <1 used for frequency above 0 and below 0.5%. Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in the placebo + BR arm. Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR. iLLUMINATE Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.
E1912 Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger. Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving IMBRUVICA E Based on laboratory measurements per IWCLL criteria. Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials (Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA.
Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. INNOVATE included 150 patients with treatment naïve or previously treated WM who received IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who received IMBRUVICA after failure of prior rituximab-containing therapy.
The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and nausea. Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reaction leading to discontinuation was atrial fibrillation.
Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94) 0 The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms. INNOVATE Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE. Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with WM in INNOVATE The body system and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms. Includes one event with a fatal outcome.
Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR. Chronic Graft versus Host Disease Study 1129 The data described below reflect exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy. The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.
Atrial fibrillation occurred in one patient (2%) which was Grade 3. Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia.
Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect exposure to IMBRUVICA with a median duration of 4.4 months in Study 7 The system organ class and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms. Includes 2 events with a fatal outcome. Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Adult Patients with cGVHD in Study 2 Treatment-emergent Grade 4 neutropenia occurred in 2% of patients. iMAGINE The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or more lines of systemic therapy. The median duration of exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).
Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis. Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis and acute respiratory distress syndrome (ARDS).
Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of patients. Adverse reactions which resulted in permanent discontinuation in at least two patients included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in 19% of patients.
Adverse reactions which required dose reduction in at least two patients included stomatitis. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache. Table 20 summarizes the adverse reactions in iMAGINE.
Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who Received IMBRUVICA in iMAGINE 2 The system organ class and individual ADR preferred terms are sorted in descending frequency order. Includes multiple ADR terms. Includes 1 fatal outcome. Table 21 summarizes the laboratory abnormalities in iMAGINE. Additional Important Adverse Reactions Cardiovascular Events Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm).
The incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. The incidence of 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. 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. Less than 1% (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.
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. 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, drug-induced liver injury 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, cutaneous vasculitis Infections: hepatitis B reactivation Nervous system disorders: peripheral neuropathy Eye disorders: uveitis
| Body System | Adverse Reaction | All Grades (%) | Grade 3 or Higher (%) |
|---|---|---|---|
| Gastrointestinal disorders | Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia | 59 22 20 20 18 14 12 | 4 2 2 0 2 0 0 |
| Skin and subcutaneous tissue disorders | Bruising Rash Petechiae | 51 25 16 | 2 0 0 |
| Infections and infestations | Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection | 47 22 16 12 12 | 2 6 6 10 2 |
| General disorders and administration site conditions | Fatigue Pyrexia Peripheral edema Asthenia Chills | 33 24 22 14 12 | 6 2 0 6 0 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain Arthralgia Muscle spasms | 25 24 18 | 6 0 2 |
| Respiratory, thoracic and mediastinal disorders | Cough Oropharyngeal pain Dyspnea | 22 14 12 | 0 0 0 |
| Nervous system disorders | Dizziness Headache | 20 18 | 0 2 |
| Vascular disorders | Hypertension | 16 | 8 |
| Metabolism and nutrition disorders | Decreased appetite | 16 | 2 |
| Neoplasms benign, malignant, unspecified | Second malignancies | 10 | 2 |
| Percent of Patients (N=51) | ||
| All Grades (%) | Grade 3 or 4 (%) | |
| Platelets decreased | 69 | 12 |
| Neutrophils decreased | 53 | 26 |
| Hemoglobin decreased | 43 | 0 |
| Body System Adverse Reaction | IMBRUVICA (N=195) | Ofatumumab (N=191) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or Higher (%) | All Grades (%) | Grade 3 or Higher (%) | |
| Gastrointestinal disorders | ||||
| Diarrhea | 48 | 4 | 18 | 2 |
| Nausea | 26 | 2 | 18 | 0 |
| Stomatitis* | 17 | 1 | 6 | 1 |
| Constipation | 15 | 0 | 9 | 0 |
| Vomiting | 14 | 0 | 6 | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 28 | 2 | 18 | 1 |
| Arthralgia | 17 | 1 | 7 | 0 |
| Muscle spasms | 13 | 0 | 8 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 24 | 3 | 13 | 0 |
| Petechiae | 14 | 0 | 1 | 0 |
| Bruising* | 12 | 0 | 1 | 0 |
| General disorders and administration site conditions | ||||
| Pyrexia | 24 | 2 | 15 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 19 | 0 | 23 | 1 |
| Dyspnea | 12 | 2 | 10 | 1 |
| Infections and infestations | ||||
| Upper respiratory tract infection | 16 | 1 | 11 | 2 |
| Pneumonia* | 15 | 12 | 13 | 10 |
| Sinusitis* | 11 | 1 | 6 | 0 |
| Urinary tract infection | 10 | 4 | 5 | 1 |
| Nervous system disorders | ||||
| Headache | 14 | 1 | 6 | 0 |
| Dizziness | 11 | 0 | 5 | 0 |
| Injury, poisoning and procedural complications | ||||
| Contusion | 11 | 0 | 3 | 0 |
| Eye disorders | ||||
| Vision blurred | 10 | 0 | 3 | 0 |
| The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Includes multiple ADR terms. Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a fatal outcome in the ofatumumab arm. | ||||
| 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 |
| Body System Adverse Reaction | IMBRUVICA (N=135) | Chlorambucil (N=132) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or Higher (%) | All Grades (%) | Grade 3 or Higher (%) | |
| Gastrointestinal disorders | ||||
| Diarrhea | 42 | 4 | 17 | 0 |
| Nausea | 22 | 1 | 39 | 1 |
| Constipation | 16 | 1 | 16 | 0 |
| Stomatitis* | 14 | 1 | 4 | 1 |
| Vomiting | 13 | 0 | 20 | 1 |
| Abdominal pain | 13 | 3 | 11 | 1 |
| Dyspepsia | 11 | 0 | 2 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 36 | 4 | 20 | 0 |
| Arthralgia | 16 | 1 | 7 | 1 |
| Muscle spasms | 11 | 0 | 5 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 30 | 1 | 38 | 5 |
| Peripheral edema | 19 | 1 | 9 | 0 |
| Pyrexia | 17 | 0 | 14 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 22 | 0 | 15 | 0 |
| Dyspnea | 10 | 1 | 10 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 21 | 4 | 12 | 2 |
| Bruising* | 19 | 0 | 7 | 0 |
| Eye disorders | ||||
| Dry eye | 17 | 0 | 5 | 0 |
| Lacrimation increased | 13 | 0 | 6 | 0 |
| Vision blurred | 13 | 0 | 8 | 0 |
| Visual acuity reduced | 11 | 0 | 2 | 0 |
| Infections and infestations | ||||
| Upper respiratory tract infection | 17 | 2 | 17 | 2 |
| Skin infection* | 15 | 2 | 3 | 1 |
| Pneumonia* | 14 | 8 | 7 | 4 |
| Urinary tract infections | 10 | 1 | 8 | 1 |
| Vascular disorders | ||||
| Hypertension* | 14 | 4 | 1 | 0 |
| Nervous system disorders | ||||
| Headache | 12 | 1 | 10 | 2 |
| Dizziness | 11 | 0 | 12 | 1 |
| Investigations | ||||
| Weight decreased | 10 | 0 | 12 | 0 |
| IMBRUVICA (N=135) | Chlorambucil (N=132) | |||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Neutrophils Decreased | 55 | 28 | 67 | 31 |
| Platelets Decreased | 47 | 7 | 58 | 14 |
| Hemoglobin Decreased | 36 | 0 | 39 | 2 |
| Body System Adverse Reaction | IMBRUVICA + BR (N=287) | Placebo + BR (N=287) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or Higher (%) | All Grades (%) | Grade 3 or Higher (%) | |
| Blood and lymphatic system disorders | ||||
| Neutropenia* | 66 | 61 | 60 | 56 |
| Thrombocytopenia* | 34 | 16 | 26 | 16 |
| Gastrointestinal disorders | ||||
| Diarrhea | 36 | 2 | 23 | 1 |
| Abdominal pain | 12 | 1 | 8 | <1 |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 32 | 4 | 25 | 1 |
| Bruising | 20 | <1 | 8 | <1 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 29 | 2 | 20 | 0 |
| Muscle spasms | 12 | <1 | 5 | 0 |
| General disorders and administration site conditions | ||||
| Pyrexia | 25 | 4 | 22 | 2 |
| Vascular disorders | ||||
| Hemorrhage* | 19 | 2 | 9 | 1 |
| Hypertension* | 11 | 5 | 5 | 2 |
| Infections and infestations | ||||
| Bronchitis | 13 | 2 | 10 | 3 |
| Skin infection* | 10 | 3 | 6 | 2 |
| Metabolism and nutrition disorders | ||||
| Hyperuricemia | 10 | 2 | 6 | 0 |
| Body System Adverse Reaction | IMBRUVICA + Obinutuzumab (N=113) | Chlorambucil + Obinutuzumab (N=115) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or Higher (%) | All Grades (%) | Grade 3 or Higher (%) | |
| Blood and lymphatic system disorders | ||||
| Neutropenia* | 48 | 39 | 64 | 48 |
| Thrombocytopenia* | 36 | 19 | 28 | 11 |
| Anemia | 17 | 4 | 25 | 8 |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 36 | 3 | 11 | 0 |
| Bruising* | 32 | 3 | 3 | 0 |
| Gastrointestinal disorders | ||||
| Diarrhea | 34 | 3 | 10 | 0 |
| Constipation | 16 | 0 | 12 | 1 |
| Nausea | 12 | 0 | 30 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 33 | 1 | 23 | 3 |
| Arthralgia | 22 | 1 | 10 | 0 |
| Muscle spasms | 13 | 0 | 6 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 27 | 1 | 12 | 0 |
| Injury, poisoning and procedural complications | ||||
| Infusion related reaction | 25 | 2 | 58 | 8 |
| Vascular disorders | ||||
| Hemorrhage* | 25 | 1 | 9 | 0 |
| Hypertension* | 17 | 4 | 4 | 3 |
| General disorders and administration site conditions | ||||
| Pyrexia | 19 | 2 | 26 | 1 |
| Fatigue | 18 | 0 | 17 | 2 |
| Peripheral edema | 12 | 0 | 7 | 0 |
| Infections and infestations | ||||
| Pneumonia* | 16 | 9 | 9 | 4 |
| Upper respiratory tract infection | 14 | 1 | 6 | 0 |
| Skin infection* | 13 | 1 | 3 | 0 |
| Urinary tract infection | 12 | 3 | 7 | 1 |
| Nasopharyngitis | 12 | 0 | 3 | 0 |
| Conjunctivitis | 11 | 0 | 2 | 0 |
| Metabolism and nutrition disorders | ||||
| Hyperuricemia | 13 | 1 | 0 | 0 |
| Cardiac disorders | ||||
| Atrial fibrillation | 12 | 5 | 0 | 0 |
| Psychiatric disorders | ||||
| Insomnia | 12 | 0 | 4 | 0 |
| Body System Adverse Reaction | IMBRUVICA + Rituximab (N=352) | Fludarabine + Cyclophosphamide + Rituximab (N=158) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or Higher (%) | All Grades (%) | Grade 3 or Higher (%) | |
| General disorders and administration site conditions | ||||
| Fatigue | 80 | 2 | 78 | 3 |
| Peripheral edema | 28 | 1 | 17 | 0 |
| Pyrexia | 27 | 1 | 27 | 1 |
| Pain | 23 | 2 | 8 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 61 | 5 | 35 | 2 |
| Arthralgia | 41 | 5 | 10 | 1 |
| Gastrointestinal disorders | ||||
| Diarrhea | 53 | 4 | 27 | 1 |
| Nausea | 40 | 1 | 64 | 1 |
| Stomatitis* | 22 | 1 | 8 | 1 |
| Abdominal pain* | 19 | 2 | 10 | 1 |
| Vomiting | 18 | 2 | 28 | 0 |
| Constipation | 17 | 0 | 32 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 49 | 4 | 29 | 5 |
| Bruising* | 36 | 1 | 4 | 1 |
| Vascular disorders | ||||
| Hypertension* | 42 | 19 | 22 | 6 |
| Hemorrhage* | 31 | 2 | 8 | 1 |
| Nervous system disorders | ||||
| Headache | 40 | 1 | 27 | 1 |
| Dizziness | 21 | 1 | 13 | 1 |
| Peripheral neuropathy* | 19 | 1 | 13 | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 32 | 0 | 25 | 0 |
| Dyspnea | 22 | 2 | 21 | 1 |
| Infections and infestations | ||||
| Upper respiratory tract | 29 | 1 | 19 | 2 |
| infection | ||||
| Skin infection* | 16 | 1 | 3 | 1 |
| Metabolism and nutrition disorders | ||||
| Hyperuricemia | 19 | 1 | 4 | 0 |
| Decreased appetite | 15 | 0 | 20 | 1 |
| Psychiatric disorders | ||||
| Insomnia | 16 | 1 | 19 | 1 |
| IMBRUVICA + Rituximab (N=352) | Fludarabine + Cyclophosphamide + Rituximab (N=158) | |||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology abnormalities Neutrophils decreased Platelets decreased Hemoglobin decreased | 53 43 26 | 30 7 0 | 70 69 51 | 44 25 2 |
| Chemistry abnormalities Creatinine increased Bilirubin increased AST increased | 38 30 25 | 1 2 3 | 17 15 23 | 1 0 <1 |
| Body System | Adverse Reaction | All Grades (%) | Grade 3 or Higher (%) |
|---|---|---|---|
| Gastrointestinal disorders | Diarrhea Nausea Stomatitis* Constipation Gastroesophageal reflux disease | 38 21 15 12 12 | 2 0 0 1 0 |
| Skin and subcutaneous tissue disorders | Bruising* Rash* | 28 21 | 1 1 |
| Vascular disorders | Hemorrhage* Hypertension* | 28 14 | 0 4 |
| General disorders and administrative site conditions | Fatigue Pyrexia | 18 12 | 2 2 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain* Muscle spasms | 21 19 | 0 0 |
| Infections and infestations | Upper respiratory tract infection Skin infection* Sinusitis* Pneumonia* | 19 18 16 13 | 0 3 0 5 |
| Nervous system disorders | Headache Dizziness | 14 13 | 0 0 |
| Respiratory, thoracic and mediastinal disorders | Cough | 13 | 0 |
| Percent of Patients (N=94) | ||
| All Grades (%) | Grade 3 or 4 (%) | |
| Platelets Decreased | 38 | 11 |
| Neutrophils Decreased | 43 | 16 |
| Hemoglobin Decreased | 21 | 6 |
| 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 |
| Body System | Adverse Reaction | All Grades (%) | Grade 3 or Higher (%) |
|---|---|---|---|
| General disorders and administration site conditions | Fatigue Pyrexia Edema peripheral | 57 17 12 | 12 5 0 |
| Skin and subcutaneous tissue disorders | Bruising* Rash* | 40 12 | 0 0 |
| Gastrointestinal disorders | Diarrhea Stomatitis* Nausea Constipation | 36 29 26 12 | 10 2 0 0 |
| Musculoskeletal and connective tissue disorders | Muscle spasms Musculoskeletal pain* | 29 14 | 2 5 |
| Vascular disorders | Hemorrhage* | 26 | 0 |
| Infections and infestations | Pneumonia* Upper respiratory tract infection Sepsis* | 21 19 10 | 14 0 10 |
| Nervous system disorders | Headache | 17 | 5 |
| Injury, poisoning and procedural complications | Fall | 17 | 0 |
| Respiratory, thoracic and mediastinal disorders | Cough Dyspnea | 14 12 | 0 2 |
| Metabolism and nutrition disorders | Hypokalemia | 12 | 7 |
| Percent of Patients (N=42) | ||
| All Grades (%) | Grade 3 or 4 (%) | |
| Platelets decreased | 33 | 0 |
| Neutrophils decreased | 10 | 10 |
| Hemoglobin decreased | 24 | 2 |
| IMBRUVICA (N=47) | ||
| Body System Adverse Reaction | All Grades (%) | Grade 3 or 4 (%) |
| General disorders and administration site conditions | ||
| Pyrexia | 30 | 11 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain* | 30 | 2 |
| Osteonecrosis | 11 | 9 |
| Gastrointestinal disorders | ||
| Diarrhea | 28 | 2 |
| Abdominal pain* | 23 | 4 |
| Stomatitis* | 23 | 9 |
| Vomiting | 19 | 2 |
| Nausea | 19 | 4 |
| Infections and infestations | ||
| Pneumonia* | 23 | 13 |
| Skin infection* | 17 | 4 |
| Sepsis* | 11 | 9 |
| Nervous system disorders | ||
| Headache | 21 | 2 |
| Skin and subcutaneous tissue disorders | ||
| Rash* | 19 | 2 |
| Pruritus | 13 | 0 |
| Petechiae | 13 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 19 | 2 |
| Vascular disorders | ||
| Hemorrhage* | 17 | 0 |
| Hypertension* | 11 | 4 |
| Blood and lymphatic system disorders | ||
| Hypokalemia | 15 | 6 |
| Hypogammaglobulinemia* | 11 | 0 |
| Cardiac Disorders | ||
| Sinus tachycardia | 11 | 0 |
| Investigations | ||
| Alanine aminotransferase increased | 11 | 2 |
| IMBRUVICA (N=47) | ||
| All Grades (%) | Grade 3 or 4 (%) | |
| Hemoglobin decreased | 49 | 13 |
| Platelets decreased | 21 | 4 |
| Neutrophils decreased | 13 | 6 |
Warnings & Cautions for Imbruvica
Hemorrhage
Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage, gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA, respectively.
The mechanism for the bleeding events is not well understood. Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage.
The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA.
Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities.
Patients with cardiac comorbidities may be at greater risk of these events. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections. Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function.
Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA treatment.
Hypertension
Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from a subset of these patients (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months).
The most frequent second primary malignancy was non-melanoma skin cancer (6%).
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including IMBRUVICA. Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA. For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.
If DILI is suspected, withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA. 5. 8 Tumor Lysis Syndrome Tumor lysis syndrome has been infrequently reported with IMBRUVICA. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.
Monitor patients closely and treat as appropriate. 5. 9 Embryo-Fetal Toxicity Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 3-20 times higher than those reported in patients with hematologic malignancies. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
Drug Interactions with Imbruvica
Effect of CYP3A Inhibitors on Ibrutinib
The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations. 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.
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). Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A.
Effect of CYP3A Inducers on Ibrutinib
The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers.
Pregnancy Safety for Imbruvica
Pregnancy Risk Summary IMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities (see Data).
Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss.
The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily.
Pediatric Use of Imbruvica
Pediatric Use Chronic GVHD The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older. Additional supportive efficacy data was provided from Study 1129 in adults. The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based on body-surface area (BSA).
The safety and effectiveness of IMBRUVICA have not been established for this indication in pediatric patients less than 1 year of age. Mature B-cell Non-Hodgkin Lymphoma The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were assessed but have not been established based on an open-label, randomized study (NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years, with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for futility.
In the randomized population, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm. CLL/SLL, CLL/SLL with 17p deletion, WM The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, or WM.
Overdosage Information for Imbruvica
There is no specific experience in the management of ibrutinib overdose in patients. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.
Clinical Studies of Imbruvica
Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one uncontrolled trial and five randomized, controlled trials. Study 1102 Study 1102 (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously treated CLL patients. IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity.
The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. All patients had a baseline ECOG performance status of 0 or 1. At baseline, 46% of subjects had at least one tumor ≥ 5 cm.
The ORR was all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months.
The median DOR was not reached. RESONATE The RESONATE study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA versus ofatumumab (NCT01578707), was conducted in patients with previously treated CLL or SLL. Fifty-seven patients randomized to ofatumumab crossed over following progression to receive IMBRUVICA.
The trial enrolled 373 patients with CLL and 18 patients with SLL. At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for RESONATE are shown in Table 22 and the Kaplan-Meier curves for PFS, assessed by an IRC according to IWCLL criteria, and OS are shown in Figure 1 and Figure 2, respectively. Table 22: Efficacy Results in Patients with CLL/SLL in RESONATE a Median OS not evaluable for either arm. b IRC evaluated. CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Figure 1: Kaplan-Meier Curve of Progression - Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with CLL/SLL in RESONATE 63-Month Follow-Up With an overall follow-up of 63 months, the median investigator-assessed PFS per IWCLL criteria was 44.1 months in the IMBRUVICA arm and 8.1 months in the ofatumumab arm. Overall response rate as assessed by investigators was 87.2% in the IMBRUVICA arm versus 22.4% in the ofatumumab arm. CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATE RESONATE included 127 patients with del 17p CLL/SLL.
PFS and ORR were assessed by an IRC. Efficacy results for del 17p CLL/SLL are shown in Table 23. Table 23: Efficacy Results in Patients with del 17p CLL/SLL in RESONATE a IRC evaluated.
Overall response rate as assessed by investigators in patients with del 17p was 88.9% in the IMBRUVICA arm versus 18.8% in the ofatumumab arm. RESONATE-2 The RESONATE-2 study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA versus chlorambucil (NCT01722487), was conducted in patients with treatment naïve CLL or SLL who were 65 years of age or older. The trial enrolled 249 patients with CLL and 20 patients with SLL.
At baseline, 20% of patients had 11q deletion. With a median follow-up of 28.1 months, there were 32 observed death events. With 41% of patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT patient population resulted in a statistically significant HR of 0.44 and 2-year survival rate estimates of 94.7% and 84.3% in the IMBRUVICA and chlorambucil arms, respectively.
Efficacy results for RESONATE-2 are shown in Table 24 and the Kaplan-Meier curve for PFS, assessed by an IRC according to IWCLL criteria is shown in Figure 3. Table 24: Efficacy Results in Patients with CLL/SLL in RESONATE-2 a IRC evaluated; five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved complete response. b HR = hazard ratio; NE = not evaluable. Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE-2 55-Month Follow-Up With an overall follow-up of 55 months, the median PFS was not reached in the IMBRUVICA arm.
HELIOS The HELIOS study, a randomized, double-blind, placebo-controlled phase 3 study of IMBRUVICA in combination with bendamustine and rituximab (BR) (NCT01611090), was conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles.
Efficacy results for HELIOS are shown in Table 25 and the Kaplan-Meier curves for PFS are shown in Figure 4. Table 25: Efficacy Results in Patients with CLL/SLL in HELIOS a IRC evaluated; twenty-four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm achieved complete response. Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in HELIOS iLLUMINATE The iLLUMINATE study, a randomized, multi-center, phase 3 study of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab (NCT02264574), was conducted in patients with treatment naïve CLL or SLL.
Patients were 65 years of age or older or < 65 years of age with coexisting medical conditions, reduced renal function as measured by creatinine clearance < 70 mL/min, or presence of del 17p/TP53 mutation. All patients had a baseline ECOG performance status of The trial enrolled 214 patients with CLL and 15 patients with SLL. At baseline, 65% of patients presented with CLL/SLL with high risk factors (del 17p/TP53 mutation, del 11q, or unmutated immunoglobulin heavy-chain variable region (unmutated IGHV) ).
The most common reasons for initiating CLL therapy included: lymphadenopathy . With a median follow-up time on study of 31 months, efficacy results for iLLUMINATE assessed by an IRC according to IWCLL criteria are shown in Table 26, and the Kaplan-Meier curve for PFS is shown in Figure 5. Table 26: Efficacy Results in Patients with CLL/SLL in iLLUMINATE is from unstratified log-rank test. c Includes 1 patient in the IMBRUVICA + obinutuzumab arm with a complete response with incomplete marrow recovery (CRi) d PR = nPR +PR.
HR = hazard ratio; NE = not evaluable. Figure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in iLLUMINATE In the high risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), the PFS HR was 0.15. E1912 The E1912 study, a randomized, multi-center, phase 3 study of IMBRUVICA in combination with rituximab versus standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy (NCT02048813), was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL requiring systemic therapy.
All patients had a CLcr > 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n =529) were randomized 2:1 to receive either IMBRUVICA plus rituximab or FCR.
Each cycle was 28 days. With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 27. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in Figure 6.
Table 27: Efficacy Results in Patients with CLL/SLL in E19 is from unstratified log-rank test. FCR = fludarabine, cyclophosphamide, and rituximab; HR = hazard ratio; R = rituximab; NE = not evaluable. Lymphocytosis Upon initiation of single-agent IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of patients in the CLL studies.
The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When IMBRUVICA was administered in combination, lymphocytosis was 7% with IMBRUVICA + BR versus 6% with placebo + BR and 7% with IMBRUVICA + obinutuzumab versus 1% with chlorambucil + obinutuzumab. 14. 2 Waldenström’s Macroglobulinemia The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-arm trials and one randomized, controlled trial. Study 1118 and INNOVATE Monotherapy Arm Study 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63 previously treated patients with WM.
The responses were assessed by investigators and an IRC using criteria adopted from the International Workshop of Waldenström’s Macroglobulinemia. At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL). Responses, defined as partial response or better, per IRC are shown in Table 28.
Table 28: Response Rate and Duration of Response (DOR) Based on IRC Assessment in Patients with WM in Study The median time to response was 1.2 months (range, 0.7-13.4 months). The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single-agent IMBRUVICA. The median age was 67 years (range, 47 to 90 years).
The median number of prior treatments was 4 (range, 1 to 7 treatments). The median duration of response was 33 months (range, 2.4 to 60.2+ months). INNOVATE The INNOVATE study, a randomized, double-blind, placebo-controlled, phase 3 study of IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in treatment naïve or previously treated patients with WM.
The major efficacy outcome measure is progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response rate. Forty-five percent of patients were treatment naïve, and 55% of patients were previously treated. Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments).
An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase of ≥ 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor support) in 65% of patients in the IMBRUVICA + R group and 39% of patients in the placebo + R group. With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the final analysis for INNOVATE are shown in Table 29, and the Kaplan-Meier curves for PFS are shown in Figure 7. Figure 7: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with WM in INNOVATE Median overall survival was not reached for either treatment arm.
Forty-seven percent of patients randomized to the placebo + R arm crossed over to receive IMBRUVICA. 14. 3 Chronic Graft versus Host Disease Study 1129 The safety and efficacy of IMBRUVICA in cGVHD were evaluated in Study 1129 (NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after failure of first line corticosteroid therapy and requiring additional therapy. The responses were assessed by investigators using the 2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two modifications to align with the updated 2014 NIH Consensus Panel Response Criteria. The most common underlying malignancies leading to transplantation were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
The median daily corticosteroid dose (prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline. Prophylaxis for infections were managed per institutional guidelines with 79% of patients receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole derivatives. Efficacy results are shown in Table 30.
Table 30: Best Overall Response Rate (ORR) and Sustained Response Rate Based on Investigator Assessment a in Patients with cGVHD in Study The median time to response coinciding with the first scheduled response assessment was 12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for cGVHD (skin, mouth, gastrointestinal tract, and liver). ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42) of patients on at least 2 consecutive visits. iMAGINE The safety and efficacy of IMBRUVICA were evaluated in iMAGINE (NCT03790332), an open-label, multi-center, single-arm trial of IMBRUVICA for the treatment of pediatric and young adult patients age 1 year to less than 22 years with moderate or severe cGVHD as defined by NIH Consensus Criteria.
The study included 47 patients who required additional therapy after failure of one or more prior lines of systemic therapy. Patients were excluded if single organ genitourinary involvement was the only manifestation of cGVHD. Concomitant treatment with supportive care therapies for cGVHD was permitted.
Initiation of new systemic cGVHD therapy while on study was not permitted. The median age was 13 years (range, 1 to 19 years). Prophylaxis for infections was managed per institutional guidelines, with 72% of patients receiving combinations of sulfonamides and trimethoprim and 70% receiving systemic antifungal agents.
The efficacy of IMBRUVICA was established based on overall response rate (ORR) through Week 25, where overall response included complete response or partial response according to the 2014 National Institutes of Health (NIH) Consensus Development Project Response Criteria. Table 31: Efficacy Results in Patients with Previously Treated cGVHD a in iMAGI = overall response rate. a Assessment based on 2014 NIH Consensus Development Project Response Criteria. b Based on all responders in the study, calculated from first response to progression, death, or new systemic therapies for cGVHD. The median time to first response was 0.9 month (range, 0.9 to 6.1 months).
The median time from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI: 4.6, not evaluable). ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in Lee Symptom Scale overall summary score through Week 25 in 50% (13/26) of patients age 12 years and older.
| Endpoint | IMBRUVICA N=195 | Ofatumumab N=196 |
|---|---|---|
| Progression - Free Survival b | ||
| Number of events (%) | 35 (17.9) | 111 (56.6) |
| Disease progression | 26 | 93 |
| Death events | 9 | 18 |
| Median (95% CI), months | NE | 8.1 (7.2, 8.3) |
| HR (95% CI) | 0.22 (0.15, 0.32) | |
| Overall Survival a | ||
| Number of deaths (%) | 16 (8.2) | 33 (16.8) |
| HR (95% CI) | 0.43 (0.24, 0.79) | |
| Overall Response Rate b | 42.6% | 4.1% |
| Endpoint | IMBRUVICA N=63 | Ofatumumab N=64 |
|---|---|---|
| Progression - Free Survival a | ||
| Number of events (%) | 16 (25.4) | 38 (59.4) |
| Disease progression | 12 | 31 |
| Death events | 4 | 7 |
| Median (95% CI), months | NE | 5.8 (5.3, 7.9) |
| HR (95% CI) | 0.25 (0.14, 0.45) | |
| Overall Response Rate a | 47.6% | 4.7% |
| Endpoint | IMBRUVICA N=136 | Chlorambucil N=133 |
|---|---|---|
| Progression - Free Survival a | ||
| Number of events (%) | 15 (11.0) | 64 (48.1) |
| Disease progression | 12 | 57 |
| Death events | 3 | 7 |
| Median (95% CI), months | NE | 18.9 (14.1, 22.0) |
| HR b (95% CI) | 0.16 (0.09, 0.28) | |
| Overall Response Rate a (CR + PR) | 82.4% | 35.3% |
| P-value | <0.0001 | |
| Endpoint | IMBRUVICA + BR N=289 | Placebo + BR N=289 |
|---|---|---|
| Progression - Free Survival a | ||
| Number of events (%) | 56 (19.4) | 183 (63.3) |
| Median (95% CI), months | NE | 13.3 (11.3, 13.9) |
| HR (95% CI) | 0.20 (0.15, 0.28) | |
| Overall Response Rate a | 82.7% | 67.8% |
| Endpoint | IMBRUVICA + Obinutuzumab N=113 | Chlorambucil + Obinutuzumab N=116 |
|---|---|---|
| Progression - Free Survival a | ||
| Number of events (%) | 24 (21) | 74 (64) |
| Disease progression | 11 | 64 |
| Death events | 13 | 10 |
| Median (95% CI), months | NE | 19.0 (15.1, 22.1) |
| HR (95% CI) | 0.23 (0.15, 0.37) | |
| P-value b | <0.0001 | |
| Overall Response Rate (%) a | 88.5 | 73.3 |
| CR c (%) | 19.5 | 7.8 |
| PR d (%) | 69.0 | 65.5 |
| Endpoint | IMBRUVICA + R N=354 | FCR N=175 |
|---|---|---|
| Progression - Free Survival | ||
| Number of events (%) | 41 (12) | 44 (25) |
| Disease progression | 39 | 38 |
| Death events | 2 | 6 |
| Median (95% CI), months | NE (49.4, NE) | NE (47.1, NE) |
| HR (95% CI) | 0.34 (0.22, 0.52) | |
| P-value a | <0.0001 | |
| Total (N=63) | |
| Response rate (CR+VGPR+PR), (%) | 61.9 |
| 95% CI (%) | (48.8, 73.9) |
| Complete Response (CR) | 0 |
| Very Good Partial Response (VGPR), (%) | 11.1 |
| Partial Response (PR), (%) | 50.8 |
| Median duration of response, months (range) | NE (2.8+, 18.8+) |
| CI = confidence interval; NE = not evaluable. | |
| Endpoint | IMBRUVICA + R N=75 | Placebo + R N=75 |
|---|---|---|
| Progression - Free Survival | ||
| Number of events (%) | 22 (29) | 50 (67) |
| Median (95% CI), months | NE (57.7, NE) | 20.3 (13.0, 27.6) |
| HR (95% CI) | 0.25 (0.15, 0.42) | |
| P-value a | <0.0001 | |
| Response Rate (CR+VGPR+PR) b | 76% | 31% |
| 95% CI (%) | (65, 85) | (21, 42) |
| Complete Response (CR) | 1% | 1% |
| Very Good Partial Response (VGPR) | 29% | 4% |
| Partial Response (PR) | 45% | 25% |
| Median duration of response, months (range) | NE (1.9+, 58.9+) | NE (4.6+, 49.7+) |
| Total (N=42) | |
| ORR | 28 (67%) |
| 95% CI | (51%, 80%) |
| Complete Response (CR) | 9 (21%) |
| Partial Response (PR) | 19 (45%) |
| Sustained response rate b | 20 (48%) |
| CI = confidence interval. a Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added “not evaluable” for organs with non-cGVHD abnormalities, and organ score change from 0 to 1 was not considered disease progression.) b Sustained response rate is defined as the proportion of patients who achieved a CR or PR that was sustained for at least 20 weeks. | |
| Total (N=47) | |
| ORR by Week 25 | 28 (60%) |
| 95% CI (%) | (44, 74) |
| Complete Response (CR) | 2 (4%) |
| Partial Response (PR) | 26 (55%) |
| Median d uration of r esponse, months (95% CI) b | 5.3 (2.8, 8.8) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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