HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`IMBRUVICA safely and effectively. See full prescribing information for
`IMBRUVICA.
`IMBRUVICA® (ibrutinib) capsules, for oral use
`IMBRUVICA® (ibrutinib) tablets, for oral use
`Initial U.S. Approval: 2013
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Dosage and Administration (2.2)
`5/2022
`Warnings and Precautions,
`Cardiac Arrhythmias, Cardiac Failure, and Sudden Death (5.3)
`Hypertension (5.4)
`
`5/2022
`5/2022
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`IMBRUVICA is a kinase inhibitor indicated for the treatment of adult patients
`with:
`• Mantle cell lymphoma (MCL) who have received at least one prior
`therapy (1.1).
`This indication is approved under accelerated approval based on overall
`response rate. Continued approval for this indication may be contingent
`upon verification and description of clinical benefit in a confirmatory
`trial(s).
`• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`(SLL) (1.2).
`• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`(SLL) with 17p deletion (1.3).
`• Waldenström’s macroglobulinemia (WM) (1.4).
`• Marginal zone lymphoma (MZL) who require systemic therapy and have
`received at least one prior anti-CD20-based therapy (1.5).
`This indication is approved under accelerated approval based on overall
`response rate. Continued approval for this indication may be contingent
`upon verification and description of clinical benefit in a confirmatory
`trial(s).
`• Chronic graft versus host disease (cGVHD) after failure of one or more
`lines of systemic therapy (1.6).
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• MCL and MZL: 560 mg taken orally once daily (2.1).
`• CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.1).
`Dose should be taken orally with a glass of water. Do not open, break, or
`chew the capsules. Do not cut, crush, or chew the tablets (2.1).
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Capsules: 70 mg and 140 mg (3)
`Tablets: 140 mg, 280 mg, 420 mg, and 560 mg (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Mantle Cell Lymphoma
`1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic
`Lymphoma
`1.3 Chronic Lymphocytic Leukemia/Small Lymphocytic
`Lymphoma with 17p deletion
`1.4 Waldenström’s Macroglobulinemia
`1.5 Marginal Zone Lymphoma
`1.6 Chronic Graft versus Host Disease
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Dosage Modifications for Adverse Reactions
`2.3 Dosage Modifications for Use with CYP3A Inhibitors
`2.4 Dosage Modifications for Use in Hepatic Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hemorrhage
`5.2
`Infections
`5.3 Cardiac Arrhythmias, Cardiac Failure, and Sudden
`Death
`5.4 Hypertension
`5.5 Cytopenias
`5.6
`Second Primary Malignancies
`5.7
`Tumor Lysis Syndrome
`5.8
`Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Postmarketing Experience
`Reference ID: 4982387
`
`
`------------------------------CONTRAINDICATIONS------------------------------
`None (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`• Hemorrhage: Monitor for bleeding and manage (5.1).
`• Infections: Monitor patients for fever and infections, evaluate promptly,
`and treat (5.2).
`• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Monitor for
`symptoms of arrhythmias and cardiac failure and manage (5.3).
`• Hypertension: Monitor blood pressure and treat (5.4).
`• Cytopenias: Check complete blood counts monthly (5.5).
`• Second Primary Malignancies: Other malignancies have occurred in
`patients, including skin cancers, and other carcinomas (5.6).
`• Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
`Monitor and treat for TLS (5.7).
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`reproductive potential of the potential risk to a fetus and to use effective
`contraception (5.8, 8.1, 8.3).
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`• The most common (≥30%) adverse reactions in patients with B-cell
`malignancies (MCL, CLL/SLL, WM and MZL) are thrombocytopenia,
`diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and
`bruising (6).
`• The most common (≥20%) adverse reactions in patients with cGVHD are
`fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis,
`nausea, hemorrhage, anemia, and pneumonia (6).
`To report SUSPECTED ADVERSE REACTIONS, contact
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
`• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1).
`• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
`(7.2).
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Lactation: Advise not to breastfeed. (8.2)
`• Hepatic Impairment (based on Child-Pugh criteria): Avoid use of
`IMBRUVICA in patients with severe hepatic impairment. In patients with
`mild or moderate impairment, reduce IMBRUVICA dose (2.4, 8.6).
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`
`
`Revised: 5/2022
`
`7
`
` DRUG INTERACTIONS
`7.1
`Effect of CYP3A Inhibitors on Ibrutinib
`7.2
`Effect of CYP3A Inducers on Ibrutinib
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7
`Plasmapheresis
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Mantle Cell Lymphoma
`14.2 Chronic Lymphocytic Leukemia / Small Lymphocytic
`Lymphoma
`14.3 Waldenström’s Macroglobulinemia
`14.4 Marginal Zone Lymphoma
`14.5 Chronic Graft versus Host Disease
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`
`1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`1.1 Mantle Cell Lymphoma
`IMBRUVICA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy.
`This indication is approved under accelerated approval based on overall response rate. Continued
`approval for this indication may be contingent upon verification and description of clinical
`benefit in a confirmatory trial(s) [see Clinical Studies (14.1)].
`1.2
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL).
`1.3
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
`1.4 Waldenström’s Macroglobulinemia
`IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
`macroglobulinemia (WM).
`1.5 Marginal Zone Lymphoma
`IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma
`(MZL) who require systemic therapy and have received at least one prior anti-CD20-based
`therapy.
`This indication is approved under accelerated approval based on overall response rate [see
`Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon
`verification and description of clinical benefit in a confirmatory trial(s).
`1.6
`Chronic Graft versus Host Disease
`IMBRUVICA is indicated for the treatment of adult patients with chronic graft-versus-host
`disease (cGVHD) after failure of one or more lines of systemic therapy.
`DOSAGE AND ADMINISTRATION
`2
`2.1
`Recommended Dosage
`Mantle Cell Lymphoma and Marginal Zone Lymphoma
`The recommended dosage of IMBRUVICA for MCL and MZL is 560 mg orally once daily until
`disease progression or unacceptable toxicity.
`
`Reference ID: 4982387
`
`2
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`

`
`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).
`For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
`When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider
`administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
`Chronic Graft versus Host Disease
`The recommended dosage of IMBRUVICA for cGVHD is 420 mg orally once daily until
`cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a
`patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be
`discontinued considering the medical assessment of the individual patient.
`Administration
`Administer IMBRUVICA at approximately the same time each day with a glass of water.
`Swallow tablets or capsule whole. Do not open, break, or chew the capsules. Do not cut, crush,
`or chew the tablets.
`If 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.
`2.2
`Dosage Modifications for Adverse Reactions
`For adverse reactions listed in Table 1, interrupt IMBRUVICA therapy. Once the adverse
`reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage
`modifications (see Table 1).
`
`Table 1: Recommended Dosage Modifications for Adverse Reactions
`Dose Modification for
`Dose Modification for
`MCL and MZL After
`CLL/SLL, WM, and
`Recovery
`cGVHD After Recovery
`Starting Dose = 560 mg
`Starting Dose = 420 mg
`
`Occurrence
`
`Adverse Reactiona,b
`
`Grade 2 cardiac failure
`
`First
`
`Second
`
`Third
`
`Restart at 420 mg dailyc
`
`Restart at 280 mg dailyc
`
`Restart at 280 mg dailyc
`
`Restart at 140 mg dailyc
`
`Discontinue IMBRUVICA Discontinue IMBRUVICA
`
`Grade 3 cardiac arrhythmias
`
`First
`
`Restart at 420 mg dailyc
`
`Restart at 280 mg dailyc
`
`3
`
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`

`

`
`
`Adverse Reactiona,b
`
`Occurrence
`
`Dose Modification for
`MCL and MZL After
`Recovery
`Starting Dose = 560 mg
`
`Dose Modification for
`CLL/SLL, WM, and
`cGVHD After Recovery
`Starting Dose = 420 mg
`
`Second
`
`Discontinue IMBRUVICA Discontinue IMBRUVICA
`
`Grade 3 or 4 cardiac failure
`Grade 4 cardiac arrhythmias
`
`First
`
`Discontinue IMBRUVICA Discontinue IMBRUVICA
`
`First
`
`Restart at 420 mg daily
`
`Restart at 280 mg daily
`
`Second
`
`Restart at 280 mg daily
`
`Restart at 140 mg daily
`
`Third
`
`Discontinue IMBRUVICA Discontinue IMBRUVICA
`
`Other Grade 3 or 4 non-
`hematological toxicitiesd
`Grade 3 or 4 neutropenia
`with infection or fever
`Grade 4 hematological
`toxicities
`a See Warnings and Precautions (5).
`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.
`2.3
`Dosage Modifications for Use with CYP3A Inhibitors
`Recommended dosage modifications are described below [see Drug Interactions (7.1)]:
`
`
`
`Reference ID: 4982387
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`
`
`
`Table 2: Recommended Dosage Modifications for Use with CYP3A Inhibitors
`
`Recommended IMBRUVICA Dosage
`280 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.2)].
`140 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.2)].
`
`70 mg once daily
`Interrupt dose as recommended [see
`Dosage and Administration (2.2)].
`
`Avoid concomitant use.
`If these inhibitors will be used short-
`term (such as anti-infectives for seven
`days or less), interrupt IMBRUVICA.
`
`420 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.2)].
`280 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.2)].
`
`140 mg once daily
`Interrupt dose as recommended [see
`Dosage and Administration (2.2)].
`
`Patient Population Coadministered Drug
`B-Cell Malignancies • Moderate CYP3A inhibitor
`
`• Voriconazole 200 mg twice daily
`• Posaconazole suspension 100 mg
`once daily, 100 mg twice daily, or
`200 mg twice daily
`• Posaconazole suspension 200 mg
`three times daily or 400 mg twice
`daily
`• Posaconazole intravenously 300 mg
`once daily
`• Posaconazole delayed-release tablets
`300 mg once daily
`• Other strong CYP3A inhibitors
`
`Chronic Graft versus
`Host Disease
`
`• Moderate CYP3A inhibitor
`
`• Voriconazole 200 mg twice daily
`• Posaconazole suspension 100 mg
`once daily, 100 mg twice daily, or
`200 mg twice daily
`
`• Posaconazole suspension 200 mg
`three times daily or 400 mg twice
`daily
`• Posaconazole intravenously 300 mg
`once daily
`• Posaconazole delayed-release tablets
`300 mg once daily
`• Other strong CYP3A inhibitors
`
`Avoid concomitant use.
`If these inhibitors will be used short-
`term (such as anti-infectives for seven
`days or less), interrupt IMBRUVICA.
`After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
`and Administration (2.1), Drug Interactions (7.1)].
`
`Reference ID: 4982387
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`

`
`Dosage Modifications for Use in Hepatic Impairment
`2.4
`The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-
`Pugh class A).
`The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-
`Pugh class B).
`Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
`[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`DOSAGE FORMS AND STRENGTHS
`3
`Capsules:
`Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
`Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
`Tablets:
`Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and
`“140” on the other side.
`Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the
`other side.
`Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and
`“420” on the other side.
`Each 560 mg tablet is a yellow to orange oblong tablet debossed with “ibr” on one side and
`“560” on the other side.
`CONTRAINDICATIONS
`4
`None
`WARNINGS AND PRECAUTIONS
`5
`5.1 Hemorrhage
`Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage
`(≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage
`[including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural
`hemorrhage) occurred in 4.2% 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 [see Adverse Reactions (6.1)].
`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
`
`6
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`Reference ID: 4982387
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`

`

`
`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 [see Clinical Studies (14)].
`5.2
`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 who
`received IMBRUVICA in clinical trials [see Adverse Reactions (6.1, 6.2)]. Cases of progressive
`multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have
`occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of
`care in patients who are at increased risk for opportunistic infections. Monitor and evaluate
`patients for fever and infections and treat appropriately.
`5.3
`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.
`Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial
`fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was
`reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in
`patients who received IMBRUVICA in unapproved monotherapy or combination regimens.
`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 [see Adverse Reactions (6.1)].
`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 [see Dosage and
`Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
`5.4 Hypertension
`Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials.
`Grade 3 or greater hypertension occurred in 8% of patients [see Adverse Reactions (6.1)]. Based
`
`Reference ID: 4982387
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`

`
`on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to
`24 months).
`Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive
`medication throughout treatment with IMBRUVICA as appropriate, and follow dosage
`modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration
`(2.2)].
`Cytopenias
`5.5
`In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3
`or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3
`or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].
`Monitor complete blood counts monthly.
`5.6
`Second Primary Malignancies
`Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the
`1,476 patients who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1)]. The
`most frequent second primary malignancy was non-melanoma skin cancer (6%).
`5.7
`Tumor Lysis Syndrome
`Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse
`Reactions (6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate
`precautions. Monitor patients closely and treat as appropriate.
`5.8
`Embryo-Fetal Toxicity
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to 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
`2-20 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.
`[see Use in Specific Populations (8.1)].
`ADVERSE REACTIONS
`6
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`• Hemorrhage [see Warnings and Precautions (5.1)]
`Infections [see Warnings and Precautions (5.2)]
`•
`• Cardiac Arrhythmias, Cardiac Failure,and Sudden Death [see Warnings and Precautions
`(5.3)]
`• Hypertension [see Warnings and Precautions (5.4)]
`• Cytopenias [see Warnings and Precautions (5.5)]
`• Second Primary Malignancies [see Warnings and Precautions (5.6)]
`
`8
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`
`
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely variable conditions, adverse event rates
`observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`another drug and may not reflect the rates observed in practice. The pooled safety population
`described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6
`trials administered as a single agent at 420 mg orally once daily (475 patients) or at 560 mg
`orally once daily (174 patients), and in 4 trials administered in combination with other drugs at
`420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled
`safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were
`exposed for greater than one year; the most common adverse reactions (≥30%) were
`thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and
`bruising.
`Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received
`IMBRUVICA in unapproved monotherapy or combination regimens.
`Mantle Cell Lymphoma
`The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that
`included 111 patients with previously treated MCL treated with 560 mg daily with a median
`treatment duration of 8.3 months.
`The most common adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia,
`anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea,
`bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Table
`3 and Table 4).
`The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
`abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
`Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in
`creatinine 1.5 to 3 times the upper limit of normal (ULN) occurred in 9% of patients.
`Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily
`occurring at a rate of ≥ 10% are presented in Table 3.
`
`
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`

`
`
`
`General disorders and
`administration site
`conditions
`
`Musculoskeletal and
`connective tissue disorders
`
`Adverse Reaction
`Body System
`Gastrointestinal disorders Diarrhea
`Nausea
`Constipation
`Abdominal pain
`Vomiting
`Stomatitis
`Dyspepsia
`Fatigue
`Peripheral edema
`Pyrexia
`Asthenia
`Musculoskeletal pain
`Muscle spasms
`Arthralgia
`Infections and infestations Upper respiratory tract infection
`Urinary tract infection
`Pneumonia
`Skin infections
`Sinusitis
`Bruising
`Rash
`Petechiae
`Dyspnea
`Cough
`Epistaxis
`Metabolism and nutrition
`Decreased appetite
`disorders
`Dehydration
`Nervous system disorders Dizziness
`Headache
`† Includes one event with a fatal outcome.
`
`
`
`Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
`All Grades
`Grade 3 or
`Higher (%)
`(%)
`51
`5
`31
`0
`25
`0
`24
`5
`23
`0
`17
`1
`11
`0
`41
`5
`35
`3
`18
`1
`14
`3
`37
`1
`14
`0
`11
`0
`34
`0
`14
`3
`14
`8†
`14
`5
`13
`1
`30
`0
`25
`3
`11
`0
`27
`5†
`19
`0
`11
`0
`21
`2
`12
`4
`14
`0
`13
`0
`
`Skin and subcutaneous
`tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
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`
`
`
`
`
`Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities
`in Patients with MCL (N=111)
`Percent of Patients (N=111)
`All Grades (%)
`Grade 3 or 4 (%)
`57
`17
`47
`29
`41
`9
`
`Platelets decreased
`Neutrophils decreased
`Hemoglobin decreased
`* 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 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).
`
`Reference ID: 4982387
`
`11
`
`

`

`
`The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%)
`were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia,
`bruising, and nausea.
`Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
`due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia,
`arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in
`approximately 9% of patients.
`Study 1102
`Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent
`IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥
`10% with a median duration of treatment of 15.6 months are presented in Table 5 and Table 6.
`
`Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`CLL/SLL (N=51) in Study 1102
`
`Body System
`Gastrointestinal disorders
`
`Skin and subcutaneous
`tissue disorders
`
`Infections and infestations
`
`General disorders and
`administration site
`conditions
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Adverse Reaction
`Diarrhea
`Constipation
`Nausea
`Stomatitis
`Vomiting
`Abdominal pain
`Dyspepsia
`Bruising
`Rash
`Petechiae
`Upper respiratory tract infection
`Sinusitis
`Skin infection
`Pneumonia
`Urinary tract infection
`Fatigue
`Pyrexia
`Peripheral edema
`Asthenia
`Chills
`Musculoskeletal pain
`Arthralgia
`Muscle spasms
`Cough
`Oropharyngeal pain
`Dyspnea
`
`All Grades
`(%)
`59
`22
`20
`20
`18
`14
`12
`51
`25
`16
`47
`22
`16
`12
`12
`33
`24
`22
`14
`12
`25
`24
`18
`22
`14
`12
`
`Grade 3 or
`Higher (%)
`4
`2
`2
`0
`2
`0
`0
`2
`0
`0
`2
`6
`6
`10
`2
`6
`2
`0
`6
`0
`6
`0
`2
`0
`0
`0
`
`12
`
`Reference ID: 4982387
`
`

`

`
`
`Body System
`Nervous system disorders
`
`Vascular disorders
`Metabolism and nutrition
`disorders
`Neoplasms benign,
`malignant, unspecified
`†One patient death due to histiocytic sarcoma.
`
`Adverse Reaction
`Dizziness
`Headache
`Hypertension
`Decreased appetite
`
`Second malignancies
`
`All Grades
`(%)
`20
`18
`16
`16
`
`Grade 3 or
`Higher (%)
`0
`2
`8
`2
`
`10
`
`2†
`
`
`
`Table 6: 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 (%)
`69
`12
`Platelets decreased
`53
`26
`Neutrophils decreased
`43
`0
`Hemoglobin decreased
`* 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.
`
`Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
`Arm in Patients with CLL/SLL in RESONATE
`
`Body System
`Adverse Reaction
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Stomatitis*
`Constipation
`Vomiting
`Musculoskeletal and
`connective tissue disorders
`Musculoskeletal pain*
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`48
`4
`26
`2
`17
`1
`15
`0
`14
`0
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`18
`2
`18
`0
`6
`1
`9
`0
`6
`1
`
`
`
`28
`
`2
`
`18
`
`1
`
`Reference ID: 4982387
`
`13
`
`

`

`
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`17
`1
`13
`0
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`7
`0
`8
`0
`
`
`
`Body System
`Adverse Reaction
`Arthralgia
`Muscle spasms
`Skin and subcutaneous tissue
`disorders
`Rash*
`Petechiae
`Bruising*
`General disorders and
`administration site conditions
`Pyrexia
`Respiratory, thoracic and
`mediastinal disorders
` Cough
` Dyspnea
`Infections and infestations
`Upper respiratory tract
`infection
`Pneumonia*
`Sinusitis*
`Urinary tract infection
`Nervous system disorders
`Headache
`Dizziness
`Injury, poisoning and
`procedural complications
`3
`0
`11
`Contusion
`Eye disorders
`
`
`
`3
`0
`10
`Vision blurred
`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.
`
`
`24
`14
`12
`
`
`24
`
`
`19
`12
`
`16
`
`15
`11
`10
`
`14
`11
`
`
`3
`0
`0
`
`
`2
`
`
`0
`2
`
`1
`
`12†
`1
`4
`
`1
`0
`
`
`13
`1
`1
`
`
`15
`
`
`23
`10
`
`11
`
`13
`6
`5
`
`6
`5
`
`
`0
`0
`0
`
`
`2†
`
`
`1
`1
`
`2†
`
`10†
`0
`1
`
`0
`0
`
`
`0
`
`0
`
`
`
`
`
`Reference ID: 4982387
`
`14
`
`

`

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