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.
`PRC-04908
`IMBRUVICA® (ibrutinib) capsules, for oral use
`IMBRUVICA® (ibrutinib) tablets, for oral use
`Initial U.S. Approval: 2013
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.6)
`01/2019
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)
`01/2019
`
`----------------------------INDICATIONS AND USAGE---------------------------
`IMBRUVICA is a kinase inhibitor indicated for the treatment of adult patients
`with:
`• Mantle cell lymphoma (MCL) who have received at least one prior
`therapy (1.1).
`Accelerated approval was granted for this indication based on overall
`response rate. Continued approval for this indication may be contingent
`upon verification and description of clinical benefit in a confirmatory
`trial.
`• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`(SLL) (1.2).
`• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`(SLL) with 17p deletion (1.3).
`• Waldenström’s macroglobulinemia (WM) (1.4).
`• Marginal zone lymphoma (MZL) who require systemic therapy and have
`received at least one prior anti-CD20-based therapy (1.5).
`Accelerated approval was granted for this indication based on overall
`response rate. Continued approval for this indication may be contingent
`upon verification and description of clinical benefit in a confirmatory trial.
`• Chronic graft versus host disease (cGVHD) after failure of one or more
`lines of systemic therapy (1.6).
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• MCL and MZL: 560 mg taken orally once daily (2.2).
`• CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.2).
`Dose should be taken orally with a glass of water. Do not open, break, or
`chew the capsules. Do not cut, crush, or chew the tablets (2.1).
`
`----------------------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 Dosing Guidelines
`2.2 Recommended Dosage
`2.3 Dose Modifications for Adverse Reactions
`2.4 Dose Modifications for Use with CYP3A Inhibitors
`2.5 Dose Modifications for Use in Hepatic Impairment
`2.6 Missed Dose
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hemorrhage
`5.2
`Infections
`5.3 Cytopenias
`5.4 Cardiac Arrhythmias
`5.5 Hypertension
`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
`
`------------------------------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).
`• Cytopenias: Check complete blood counts monthly (5.3).
`• Cardiac arrhythmias: Monitor for symptoms of arrhythmias and manage
`(5.4).
`• Hypertension: Monitor blood pressure and treat (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 women of the
`potential risk to a fetus and to avoid pregnancy while taking the drug and
`for 1 month after cessation of therapy. Advise men to avoid fathering a
`child during the same time period (5.8, 8.3).
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions (≥20%) in patients with B-cell
`malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia,
`diarrhea, anemia, neutropenia, musculoskeletal pain, rash, bruising, nausea,
`fatigue, hemorrhage, and pyrexia (6).
`The most common adverse reactions (≥20%) in patients with cGVHD were
`fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis,
`nausea, hemorrhage, anemia, and pneumonia (6).
`To report SUSPECTED ADVERSE REACTIONS, contact
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
`• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.4, 7.1).
`• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
`(7.2).
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Hepatic Impairment (based on Child-Pugh criteria): Avoid use of
`IMBRUVICA in patients with severe baseline hepatic impairment. In patients
`with mild or moderate impairment, reduce IMBRUVICA dose (2.5, 8.6).
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 01/2019
`
`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.
`Accelerated approval was granted for this indication based on overall response rate. Continued
`approval for this indication may be contingent upon verification and description of clinical
`benefit in a confirmatory trial [see Clinical Studies (14.1)].
`1.2
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL).
`1.3
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
`1.4 Waldenström’s Macroglobulinemia
`IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
`macroglobulinemia (WM).
`1.5 Marginal Zone Lymphoma
`IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma
`(MZL) who require systemic therapy and have received at least one prior anti-CD20-based
`therapy.
`Accelerated approval was granted for this indication based on overall response rate [see Clinical
`Studies (14.4)]. Continued approval for this indication may be contingent upon verification and
`description of clinical benefit in a confirmatory trial.
`1.6
`Chronic Graft versus Host Disease
`IMBRUVICA is indicated for the treatment of adult patients with chronic graft-versus-host
`disease (cGVHD) after failure of one or more lines of systemic therapy.
`DOSAGE AND ADMINISTRATION
`2
`2.1
`Dosing Guidelines
`Administer IMBRUVICA orally once daily at approximately the same time each day. The dose
`should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not
`cut, crush, or chew the tablets.
`
`2
`
`

`

`
`
`Recommended Dosage
`2.2
`Mantle Cell Lymphoma and Marginal Zone Lymphoma
`The recommended dose of IMBRUVICA for MCL and MZL is 560 mg orally once daily until
`disease progression or unacceptable toxicity.
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
`Macroglobulinemia
`The recommended dose of IMBRUVICA for CLL/SLL and WM as a single agent, in
`combination with rituximab for WM, or in combination with bendamustine and rituximab or
`with obinutuzumab for CLL/SLL is 420 mg orally once daily until disease progression or
`unacceptable toxicity.
`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 dose of IMBRUVICA for cGVHD is 420 mg orally once daily until cGVHD
`progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient
`no longer requires therapy for the treatment of cGVHD, IMBRUVICA should be discontinued
`considering the medical assessment of the individual patient.
`2.3
`Dose Modifications for Adverse Reactions
`Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological toxicities, Grade 3
`or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the
`symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy
`may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by 140 mg per day. A
`second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or
`recur following two dose reductions, discontinue IMBRUVICA.
`Recommended dose modifications are described below:
`
`Toxicity Occurrence
`First
`Second
`Third
`Fourth
`
`Dose Modification for MCL and
`MZL After Recovery
`Starting Dose = 560 mg
`Restart at 560 mg daily
`Restart at 420 mg daily
`Restart at 280 mg daily
`Discontinue IMBRUVICA
`
`Dose Modification for CLL/SLL,
`WM, and cGVHD After Recovery
`Starting Dose = 420 mg
`Restart at 420 mg daily
`Restart at 280 mg daily
`Restart at 140 mg daily
`Discontinue IMBRUVICA
`
`3
`
`

`

`
`
`Dose Modifications for Use with CYP3A Inhibitors
`2.4
`Recommended dose modifications are described below [see Drug Interactions (7.1)]:
`
`Recommended IMBRUVICA Dose
`280 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.3)].
`
`140 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.3)].
`
`70 mg once daily
`Interrupt dose as recommended [see
`Dosage and Administration (2.3)].
`
`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 (2.3)].
`280 mg once daily
`Modify dose as recommended [see
`Dosage and Administration (2.3)].
`
`140 mg once daily
`Interrupt dose as recommended [see
`Dosage and Administration (2.3)].
`
`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 IV injection 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 IV injection 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 (2.2) and Drug Interactions (7.1)].
`
`4
`
`

`

`
`Dose Modifications for Use in Hepatic Impairment
`2.5
`The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh
`class A).
`The recommended dose is 70 mg daily for patients with moderate hepatic impairment (Child-
`Pugh class B).
`Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
`[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`2.6 Missed Dose
`If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
`on the same day with a return to the normal schedule the following day. Extra doses of
`IMBRUVICA should not be taken to make up for the missed dose.
`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 treated with IMBRUVICA. Grade 3 or higher
`bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal
`bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with
`fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA in clinical trials. Bleeding
`events of any grade, including bruising and petechiae, occurred in 44% of patients treated with
`IMBRUVICA.
`
`5
`
`

`

`
`The mechanism for the bleeding events is not well understood.
`IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or
`anticoagulant therapies and patients should be monitored for signs 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 24% of 1,124 patients exposed
`to 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
`Cytopenias
`Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia
`(8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell
`malignancies treated with single agent IMBRUVICA.
`Monitor complete blood counts monthly.
`5.4
`Cardiac Arrhythmias
`Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or
`greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial
`fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in
`clinical trials. These events have occurred particularly in patients with cardiac risk factors,
`hypertension, acute infections, and a previous history of cardiac arrhythmias. See Additional
`Important Adverse Reactions (6.1).
`Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who
`develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new
`onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks
`and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage
`and Administration (2.3)].
`5.5 Hypertension
`Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in
`clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to
`onset of 5.9 months (range, 0.03 to 24 months).
`Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-
`hypertensive medication throughout treatment with IMBRUVICA as appropriate.
`
`6
`
`

`

`
`Second Primary Malignancies
`5.6
`Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients
`treated with IMBRUVICA in clinical trials. 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 therapy. 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 women
`to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of
`therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking
`this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific
`Populations (8.1)].
`ADVERSE REACTIONS
`6
`The following clinically significant adverse reactions are discussed in more detail in other
`sections of the labeling:
`• Hemorrhage [see Warnings and Precautions (5.1)]
`Infections [see Warnings and Precautions (5.2)]
`•
`• Cytopenias [see Warnings and Precautions (5.3)]
`• Cardiac Arrhythmias [see Warnings and Precautions (5.4)]
`• Hypertension [see Warnings and Precautions (5.5)]
`• Second Primary Malignancies [see Warnings and Precautions (5.6)]
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
`6.1
`Clinical Trials Experience
`Because clinical trials are conducted under widely variable conditions, adverse event rates
`observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`another drug and may not reflect the rates observed in practice.
`
`7
`
`

`

`
`Mantle Cell Lymphoma
`The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that
`included 111 patients with previously treated MCL treated with 560 mg daily with a median
`treatment duration of 8.3 months.
`The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
`neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract
`infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased
`appetite (see Tables 1 and 2).
`The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
`abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
`Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in
`creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.
`Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily
`occurring at a rate of ≥ 10% are presented in Table 1.
`
`Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
`
`Adverse Reaction
`Body System
`Gastrointestinal disorders Diarrhea
`Nausea
`Constipation
`Abdominal pain
`Vomiting
`Stomatitis
`Dyspepsia
`Infections and infestations Upper respiratory tract infection
`Urinary tract infection
`Pneumonia
`Skin infections
`Sinusitis
`Fatigue
`Peripheral edema
`Pyrexia
`Asthenia
`Bruising
`Rash
`Petechiae
`Musculoskeletal pain
`Muscle spasms
`Arthralgia
`Dyspnea
`Cough
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`General disorders and
`administration site
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`All Grades
`(%)
`51
`31
`25
`24
`23
`17
`11
`34
`14
`14
`14
`13
`41
`35
`18
`14
`30
`25
`11
`37
`14
`11
`27
`19
`
`Grade 3 or
`Higher (%)
`5
`0
`0
`5
`0
`1
`0
`0
`3
`8†
`5
`1
`5
`3
`1
`3
`0
`3
`0
`1
`0
`0
`5†
`0
`
`8
`
`

`

`
`
`Body System
`
`Adverse Reaction
`
`Metabolism and nutrition
`disorders
`Nervous system disorders
`
`Epistaxis
`Decreased appetite
`Dehydration
`Dizziness
`Headache
`† Includes one event with a fatal outcome.
`
`All Grades
`(%)
`11
`21
`12
`14
`13
`
`Grade 3 or
`Higher (%)
`0
`2
`4
`0
`0
`
`Table 2: 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 in one single-arm, open-label clinical trial
`(Study 1102) and four randomized controlled clinical trials (RESONATE, RESONATE-2, and
`HELIOS, and iLLUMINATE) in patients with CLL/SLL (n=1,506 total and n=781 patients
`exposed to IMBRUVICA). Patients with creatinine clearance (CrCl) ≤ 30 mL/min, AST or ALT
`≥ 2.5 x ULN (upper limit of normal), or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin)
`were excluded from these trials. Study 1102 included 51 patients with previously treated
`CLL/SLL, RESONATE included 386 randomized patients with previously treated CLL or SLL
`who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included
`267 randomized patients with treatment naïve-CLL or SLL who were 65 years or older and
`received single agent IMBRUVICA or chlorambucil, HELIOS included 574 randomized patients
`with previously treated CLL or SLL who received IMBRUVICA in combination with
`bendamustine and rituximab or placebo in combination with bendamustine and rituximab, and
`
`9
`
`

`

`
`iLLUMINATE included 228 randomized patients with treatment naïve CLL who were 65 years
`or older or with coexisting medical conditions and received IMBRUVICA in combination with
`obinutuzumab or chlorambucil in combination with obinutuzumab.
`The most commonly occurring adverse reactions in patients with CLL/SLL receiving
`IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, rash,
`musculoskeletal pain, bruising, nausea, fatigue, pyrexia, hemorrhage, and cough.
`Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
`due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and
`neutropenia. Adverse reactions leading to dose reduction occurred in approximately 7% of
`patients.
`Study 1102
`Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single
`agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a
`rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3
`and 4.
`
`Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`CLL/SLL (N=51) in Study 1102
`
`Body System
`Gastrointestinal disorders
`
`Infections and infestations
`
`General disorders and
`administration site
`conditions
`
`Skin and subcutaneous tissue
`disorders
`
`Respiratory, thoracic and
`
`Adverse Reaction
`Diarrhea
`Constipation
`Nausea
`Stomatitis
`Vomiting
`Abdominal pain
`Dyspepsia
`Upper respiratory tract infection
`Sinusitis
`Skin infection
`Pneumonia
`Urinary tract infection
`Fatigue
`Pyrexia
`Peripheral edema
`Asthenia
`Chills
`Bruising
`Rash
`Petechiae
`Cough
`
`All Grades
`(%)
`59
`22
`20
`20
`18
`14
`12
`47
`22
`16
`12
`12
`33
`24
`22
`14
`12
`51
`25
`16
`22
`
`Grade 3 or
`Higher (%)
`4
`2
`2
`0
`2
`0
`0
`2
`6
`6
`10
`2
`6
`2
`0
`6
`0
`2
`0
`0
`0
`
`10
`
`

`

`
`
`Body System
`mediastinal disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Nervous system disorders
`
`Adverse Reaction
`Oropharyngeal pain
`Dyspnea
`Musculoskeletal pain
`Arthralgia
`Muscle spasms
`Dizziness
`Headache
`Decreased appetite
`
`Metabolism and nutrition
`disorders
`Neoplasms benign,
`malignant, unspecified
`Vascular disorders
`Hypertension
`†One patient death due to histiocytic sarcoma.
`
`Second malignancies
`
`All Grades
`(%)
`14
`12
`25
`24
`18
`20
`18
`16
`
`10
`
`16
`
`Grade 3 or
`Higher (%)
`0
`0
`6
`0
`2
`0
`2
`2
`
`2†
`
`8
`
`Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities
`in Patients with CLL/SLL (N=51) in Study 1102
`
`
`
`Percent of Patients (N=51)
`All Grades (%)
`Grade 3 or 4 (%)
`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 Tables 5 and 6 reflect
`exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
`with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.
`
`Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE
`
`Body System
`Adverse Reaction
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Stomatitis*
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`48
`4
`26
`2
`17
`1
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`18
`2
`18
`0
`6
`1
`
`11
`
`

`

`
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`15
`0
`14
`0
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`9
`0
`6
`1
`
`
`
`Body System
`Adverse Reaction
`Constipation
`Vomiting
`General disorders and
`administration site conditions
`Pyrexia
`Infections and infestations
`Upper respiratory tract
`infection
`Pneumonia*
`Sinusitis*
`Urinary tract infection
`Skin and subcutaneous tissue
`disorders
`Rash*
`Petechiae
`Bruising*
`Musculoskeletal and
`connective tissue disorders
`Musculoskeletal pain*
`Arthralgia
`Nervous system disorders
`Headache
`Dizziness
`Injury, poisoning and
`procedural complications
`3
`0
`11
`Contusion
`Eye disorders
`
`
`
`3
`0
`10
`Vision blurred
`Subjects with multiple events for a given adverse reaction (ADR) term are counted once only for each ADR term.
`The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`* Includes multiple ADR terms
`† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a
`fatal outcome in the ofatumumab arm.
`
`24
`
`16
`
`15
`11
`10
`
`
`24
`14
`12
`
`
`28
`17
`
`14
`11
`
`
`2
`
`1
`
`12†
`1
`4
`
`
`3
`0
`0
`
`
`2
`1
`
`1
`0
`
`
`15
`
`11
`
`13
`6
`5
`
`
`13
`1
`1
`
`
`18
`7
`
`6
`5
`
`
`2†
`
`2†
`
`10†
`0
`1
`
`
`0
`0
`0
`
`
`1
`0
`
`0
`0
`
`
`0
`
`0
`
`Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
`CLL/SLL in RESONATE
`
`
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`
`12
`
`

`

`
`
`(%)
`(%)
`(%)
`(%)
`26
`57
`23
`51
`Neutrophils Decreased
`10
`45
`5
`52
`Platelets Decreased
`0
`21
`0
`36
`Hemoglobin Decreased
`Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia
`(8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.
`
`RESONATE-2
`Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median
`duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in
`RESONATE-2.
`
`Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2
`
`Body System
`Adverse Reaction
`Gastrointestinal disorders
` Diarrhea
` Stomatitis*
`Musculoskeletal and
`connective tissue disorders
` Musculoskeletal pain*
` Arthralgia
` Muscle spasms
`Eye disorders
` Dry eye
` Lacrimation increased
` Vision blurred
` Visual acuity reduced
`Skin and subcutaneous tissue
`disorders
` Rash*
` Bruising*
`Infections and infestations
` Skin infection*
` Pneumonia*
` Urinary tract infections
`Respiratory, thoracic and
`mediastinal disorders
` Cough
`
`IMBRUVICA
`(N=135)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`42
`4
`14
`1
`
`
`36
`4
`16
`1
`11
`0
`
`
`17
`0
`13
`0
`13
`0
`11
`0
`
`
`21
`4
`19
`0
`
`
`15
`2
`14
`8
`10
`1
`
`
`22
`0
`
`Chlorambucil
`(N=132)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`17
`0
`4
`1
`
`
`20
`0
`7
`1
`5
`0
`
`
`5
`0
`6
`0
`8
`0
`2
`0
`
`
`12
`2
`7
`0
`
`
`3
`1
`7
`4
`8
`1
`
`
`15
`0
`
`13
`
`

`

`
`
`Chlorambucil
`IMBRUVICA
`(N=132)
`(N=135)
`Body System
`All Grades
`Grade 3 or
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`(%)
`Higher (%)
`Adverse Reaction
`General disorders and
`
`
`
`
`administration site conditions
` Peripheral edema
`9
`0
`19
`1
`14
`2
`17
`0
` Pyrexia
`Vascular disorders
`
`
`
`
` Hypertension*
`1
`0
`14
`4
`Nervous system disorders
`
`
`
`
` Headache
`10
`2
`12
`1
`Subjects with multiple events for a given ADR term are counted once only for each ADR term.
`The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`* Includes multiple ADR terms
`
`HELIOS
`Adverse reactions described below in Table 8 reflect exposure to IMBRUVICA + BR with a
`median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in
`HELIOS in patients with previously treated CLL/SLL.
`
`Table 8: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater
`in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS
`
`Body System
`Adverse Reaction
`Blood and lymphatic
`system disorders
` Neutropenia*
` Thrombocytopenia*
`Skin and subcutaneous
`tissue disorders
` Rash *
` Bruising *
`Gastrointestinal disorders
` Diarrhea
` Abdominal pain
`
`Ibrutinib + BR
`(N=287)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`66
`34
`
`32
`20
`
`36
`12
`
`
`2
`1
`
`
`61
`16
`
`
`4
`<1
`
`Placebo + BR
`(N=287)
`All Grades
`Grade 3 or
`(%)
`Higher (%)
`
`
`60
`26
`
`
`25
`8
`
`
`23
`8
`
`
`56†
`16
`
`
`1
`<1
`
`
`1
`<1
`
`14
`
`

`

`
`29
`12
`
`
`
`
`2
`<1
`
`
`4
`
`
`2†
`5
`
`
`2
`3
`
`
`Musculoskeletal and
`connective tissue disorders
` Musculoskeletal pain*
` Muscle spasms
`General disorders and
`administration site
`conditions
` Pyrexia
`25
`Vascular disorders
`
`19
` Hemorrhage*
`11
`Hypertension *
`Infections and infestations
`
` Bronchitis
`13
` Skin infection*
`10
`Metabolism and nutrition
`
`disorders
`
`
`Hyperuricemia
`6
`2
`10
`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 f