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
`Initial U.S. Approval: 2013
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1.2, 1.3)
`
`5/2016
`Dosage and Administration (2.2)
`
`5/2016
`Warnings and Precautions (5)
`
`
`3/2016
`----------------------------INDICATIONS AND USAGE---------------------------
`IMBRUVICA is a kinase inhibitor indicated for the treatment of 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 of clinical benefit in confirmatory trials.
`• 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).
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• MCL: 560 mg taken orally once daily (four 140 mg capsules once daily)
`(2.2).
`• CLL/SLL and WM: 420 mg taken orally once daily (three 140 mg
`capsules once daily) (2.2).
`Capsules should be taken orally with a glass of water. Do not open, break, or
`chew the capsules (2.1).
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Capsule: 140 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`• Hemorrhage: Monitor for bleeding and manage (5.1).
`
`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
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`2.2 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 Atrial Fibrillation
`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
`7 DRUG INTERACTIONS
`
`Reference ID: 3952152
`
`• Infections: Monitor patients for fever and infections, evaluate promptly,
`and treat (5.2).
`• Cytopenias: Check complete blood counts monthly (5.3).
`• Atrial Fibrillation: Monitor for atrial fibrillation 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, and WM) were neutropenia,
`thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea,
`bruising, fatigue, hemorrhage, and pyrexia (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: Avoid co-administration with strong and moderate
`CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce
`IMBRUVICA dose (2.4, 7.1).
`• CYP3A Inducers: Avoid co-administration with strong CYP3A inducers
`(7.2).
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Hepatic Impairment (based on Child-Pugh criteria): Avoid use of
`IMBRUVICA in patients with moderate or severe baseline hepatic
`impairment. In patients with mild impairment, reduce IMBRUVICA dose
`(2.5, 8.6).
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 6/2016
`
`
`
`7.1 CYP3A Inhibitors
`7.2 CYP3A Inducers
`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
`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 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 of clinical benefit in
`confirmatory trials [see Clinical Studies (14.1)].
`1.2
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) [see Clinical Studies (14.2)].
`1.3
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion [see Clinical Studies (14.2)].
`1.4 Waldenström’s Macroglobulinemia
`IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia
`(WM) [see Clinical Studies (14.3)].
`DOSAGE AND ADMINISTRATION
`2
`2.1
`Dosing Guidelines
`Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow
`the capsules whole with water. Do not open, break, or chew the capsules.
`2.2
`Dosage
`Mantle Cell Lymphoma
`The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) 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 is 420 mg (three 140 mg
`capsules) orally once daily until disease progression or unacceptable toxicity.
`The recommended dose of IMBRUVICA for CLL/SLL when used in combination with
`bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg (three
`140 mg capsules) orally once daily until disease progression or unacceptable toxicity.
`
`
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`Dose Modifications for Adverse Reactions
`2.3
`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 one capsule
`(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
`
`MCL Dose Modification After
`Recovery
`Starting Dose = 560 mg
`Restart at 560 mg daily
`Restart at 420 mg daily
`Restart at 280 mg daily
`Discontinue IMBRUVICA
`
`CLL/SLL and WM Dose
`Modification After Recovery
`Starting Dose = 420 mg
`Restart at 420 mg daily
`Restart at 280 mg daily
`Restart at 140 mg daily
`Discontinue IMBRUVICA
`
`Dose Modifications for Use with CYP3A Inhibitors
`2.4
`Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative
`agents with less CYP3A inhibition.
`Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir,
`indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For
`short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and
`antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer
`needed [see Drug Interactions (7.1)].
`Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g.,
`fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir,
`crizotinib, imatinib, verapamil, and ciprofloxacin) [see Drug Interactions (7.1)].
`Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more
`closely for signs of IMBRUVICA toxicity.
`
`Dose Modifications for Use in Hepatic Impairment
`2.5
`For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg
`daily (one capsule). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic
`impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.6) and Clinical
`Pharmacology (12.3)].
`
`
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`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 capsules of
`IMBRUVICA should not be taken to make up for the missed dose.
`
`DOSAGE FORMS AND STRENGTHS
`3
`140 mg capsules
`
`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 up to 6% of patients.
`Bleeding events of any grade, including bruising and petechiae, occurred in approximately half
`of patients treated with IMBRUVICA.
`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 have occurred with IMBRUVICA therapy. Grade 3 or greater
`infections occurred in 14% to 29% of patients [see Adverse Reactions (6.1), (6.2)]. Cases of
`progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with
`IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.
`5.3
`Cytopenias
`Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%),
`thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) based on laboratory
`measurements occurred in patients treated with single agent IMBRUVICA.
`Monitor complete blood counts monthly.
`5.4
`Atrial Fibrillation
`Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with
`IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections,
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`and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial
`fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or
`new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed
`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 (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a
`median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset
`hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.
`Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as
`appropriate.
`5.6
`Second Primary Malignancies
`Other malignancies (range, 5 to 16%) including non-skin carcinomas (range, 1 to 4%) have
`occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy
`was non-melanoma skin cancer (range, 4 to 13%).
`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 embryofetal toxicity including malformations at exposures that were 2-20
`times higher than those reported in patients with MCL, CLL/SLL or WM. 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 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)]
`• Atrial Fibrillation [see Warnings and Precautions (5.4)]
`• Hypertension [see Warnings and Precautions (5.5)]
`
`5
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`
`
`• Second Primary Malignancies [see Warnings and Precautions (5.6)]
`• 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.
`Mantle Cell Lymphoma
`The data described below reflect exposure to IMBRUVICA in a clinical trial 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.
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`
`Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`MCL (N=111)
`
`Grade 3 or 4 (%)
`5
`0
`0
`5
`0
`1
`0
`
` 0
`
`
`3
`7
`5
`1
`5
`3
`1
`3
`0
`3
`0
`1
`0
`0
`4
`0
`0
`2
`4
`0
`0
`
`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
`11
`21
`12
`14
`13
`
`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
`Epistaxis
`Decreased appetite
`Dehydration
`Dizziness
`Headache
`
`General disorders and
`administration site
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Metabolism and nutrition
`disorders
`Nervous system disorders
`
`
`
`
`
`Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with MCL (N=111)
`
`Platelets Decreased
`Neutrophils Decreased
`Hemoglobin Decreased
`* Based on laboratory measurements and adverse reactions
`
`Percent of Patients (N=111)
`All Grades (%)
`Grade 3 or 4 (%)
`57
`17
`47
`29
`41
`9
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`
`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 and three
`randomized controlled clinical trials in patients with CLL/SLL (n=1278 total and n=668 patients
`exposed to IMBRUVICA). Study 1 included 51 patients with previously treated CLL/SLL, Study
`2 included 391 randomized patients with previously treated CLL or SLL who received single
`agent IMBRUVICA or ofatumumab, Study 3 included 269 randomized patients 65 years or older
`with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil and
`Study 4 included 578 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.
`The most commonly occurring adverse reactions in Studies 1, 2, 3 and 4 in patients with
`CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia,
`diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to
`10 percent of patients receiving IMBRUVICA in Studies 1, 2, 3 and 4 discontinued treatment
`due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and
`neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately
`6% of patients.
`Study 1
`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.
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`Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`CLL/SLL (N=51) in Study 1
`
`Body System
`Gastrointestinal disorders
`
`Infections and infestations
`
`General disorders and
`administration site
`conditions
`
`Skin and subcutaneous tissue
`disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Nervous system disorders
`
`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
`Oropharyngeal pain
`Dyspnea
`Musculoskeletal pain
`Arthralgia
`Muscle spasms
`Dizziness
`Headache
`
`Decreased appetite
`
`Metabolism and nutrition
`disorders
`Neoplasms benign,
`malignant, unspecified
`Hypertension
`Vascular disorders
`*One patient death due to histiocytic sarcoma.
`
`
`
`Second malignancies*
`
`All Grades (%)
`59
`22
`20
`20
`18
`14
`12
`47
`22
`16
`12
`12
`33
`24
`22
`14
`12
`51
`25
`16
`22
`14
`12
`25
`24
`18
`20
`18
`
`16
`
`Grade 3 or 4
`(%)
`4
`2
`2
`0
`2
`0
`0
`2
`6
`6
`10
`2
`6
`2
`0
`6
`0
`2
`0
`0
`0
`0
`0
`6
`0
`2
`0
`2
`
`2
`
`12*
`
`16
`
`0
`
`8
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`
`
`Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with CLL/SLL (N=51) in Study 1
`
`
`
`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.
`
`Study 2
`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 Study 2 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 in Study 2
`
`Body System
`Adverse Reaction
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Stomatitis*
`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*
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`48
`4
`26
`2
`17
`1
`15
`0
`14
`0
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`18
`2
`18
`0
`6
`1
`9
`0
`6
`1
`
`
`
`24
`
`16
`
`15
`11
`10
`
`
`24
`14
`12
`
`2
`
`1
`
`10
`1
`4
`
`
`3
`0
`0
`
`15
`
`11
`
`13
`6
`5
`
`
`13
`1
`1
`
`1
`
`2
`
`9
`0
`1
`
`
`0
`0
`0
`
`10
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`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`
`Body System
`Adverse Reaction
`Musculoskeletal and
`connective tissue disorders
`Musculoskeletal Pain*
`Arthralgia
`Nervous system disorders
`Headache
`Dizziness
`Injury, poisoning and
`procedural complications
`0
`11
`Contusion
`Eye disorders
`
`
`0
`10
`Vision blurred
`Subjects with multiple events for a given ADR term are counted once only for each ADR term.
`The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`* Includes multiple ADR terms
`
`28
`17
`
`14
`11
`
`
`2
`1
`
`1
`0
`
`
`18
`7
`
`6
`5
`
`
`3
`
`3
`
`1
`0
`
`0
`0
`
`
`0
`
`0
`
`
`
`Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Study 2
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`51
`23
`Neutrophils Decreased
`52
`5
`Platelets Decreased
`36
`0
`Hemoglobin Decreased
`* Based on laboratory measurements per IWCLL criteria.
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`57
`26
`45
`10
`21
`0
`
`Study 3
`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 Study 3.
`
`Reference ID: 3952152
`
`11
`
`

`

`
`
`Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`IMBRUVICA Treated Arm in Patients in Study 3
`IMBRUVICA
`Chlorambucil
`(N=135)
`(N=132)
`Body System
`All Grades
`Grade 3 or 4
`All Grades
`Grade 3 or 4
`(%)
`(%)
`(%)
`(%)
`Adverse Reaction
`Gastrointestinal disorders
`
`
`
`
`42
`4
`17
`0
` Diarrhea
`14
`1
`4
`1
` Stomatitis*
`Musculoskeletal and
`
`
`
`
`connective tissue disorders
`36
`4
`20
`0
` Musculoskeletal pain*
`16
`1
`7
`1
` Arthralgia
`11
`0
`5
`0
` Muscle spasms
`Eye Disorders
`
`
`
`
`17
`0
`5
`0
` Dry eye
`13
`0
`6
`0
` Lacrimation increased
`13
`0
`8
`0
` Vision blurred
`11
`0
`2
`0
` Visual acuity reduced
`Skin and subcutaneous tissue
`
`
`
`
`disorders
`21
`4
`12
`2
` Rash*
`19
`0
`7
`0
` Bruising*
`Infections and infestations
`
`
`
`
`15
`2
`3
`1
` Skin infection*
`14
`8
`7
`4
` Pneumonia*
`10
`1
`8
`1
` Urinary tract infections
`Respiratory, thoracic and
`
`
`
`
`mediastinal disorders
`22
`0
`15
`0
` Cough
`General disorders and
`
`
`
`
`administration site conditions
` Peripheral edema
`19
`1
`9
`0
`17
`0
`14
`2
` Pyrexia
`Vascular Disorders
`
`
`
`
` Hypertension*
`14
`4
`1
`0
`Nervous System Disorders
`
`
`
`
` Headache
`12
`1
`10
`2
`Subjects with multiple events for a given ADR term are counted once only for each ADR term.
`The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`* Includes multiple ADR terms
`
`
`Reference ID: 3952152
`
`12
`
`

`

`
`Study 4
`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
`Study 4 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 in Study 4
`
`Ibrutinib + BR
`(N=287)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`66
`34
`
`
`61
`16
`
`
`4
`<1
`
`
`2
`1
`
`
`2
`<1
`
`
`4
`
`
`2
`5
`
`
`2
`3
`
`
`
`25
`
`19
`11
`
`13
`10
`
`Placebo + BR
`(N=287)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`60
`26
`
`
`25
`8
`
`
`23
`8
`
`
`20
`5
`
`
`22
`
`
`9
`5
`
`
`10
`6
`
`
`55
`16
`
`
`1
`<1
`
`
`1
`<1
`
`
`0
`0
`
`
`2
`
`
`1
`2
`
`
`3
`2
`
`Body System
`Adverse Reaction
`Blood and lymphatic
`system disorders
` Neutropenia*
` Thrombocytopenia*
`Skin and subcutaneous
`
`tissue disorders
` Rash *
`32
` Bruising *
`20
`Gastrointestinal disorders
` Diarrhea
`36
` Abdominal Pain
`12
`Musculoskeletal and
`
`connective tissue disorders
` Musculoskeletal pain * 29
` Muscle spasms 12
`General disorders and
`administration site
`conditions
` Pyrexia
`Vascular Disorders
` Hemorrhage*
`Hypertension *
`Infections and infestations
` Bronchitis
` Skin infection*
`Metabolism and nutrition
`
`disorders
`
`
`
`Hyperuricemia
`0
`6
`2
`10
`The system organ class 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%
`
`Reference ID: 3952152
`
`13
`
`

`

`
`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.
`Waldenström’s Macroglobulinemia
`The data described below reflect exposure to IMBRUVICA in an open-label clinical trial that
`included 63 patients with previously treated WM.
`The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia,
`thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
`Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to
`adverse events. Adverse events leading to dose reduction occurred in 11% of patients.
`Adverse reactions and laboratory abnormalities described below in Tables 9 and 10 reflect
`exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.
`
`Table 9: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`Waldenström’s Macroglobulinemia (N=63)
`All Grades
`(%)
`37
`21
`16
`13
`22
`16
`11
`21
`
`Neoplasms benign, malignant,
`and unspecified (including cysts
`and polyps)
`The system organ class and individual ADR preferred terms are sorted in descending frequency order.
`* Includes multiple ADR terms.
`
`
`
`
`Reference ID: 3952152
`
`Body System
`Gastrointestinal disorders
`
`Skin and subcutaneous tissue
`disorders
`
`General disorders and
`administrative site conditions
`Musculoskeletal and connective
`tissue disorders
`Infections and infestations
`
`Respiratory, thoracic and
`mediastinal disorders
`Nervous system disorders
`
`Adverse Reaction
`Diarrhea
`Nausea
`Stomatitis*
`Gastroesophageal reflux disease
`Rash*
`Bruising*
`Pruritus
`Fatigue
`
`Muscle spasms
`Arthropathy
`Upper respiratory tract infection
`Sinusitis
`Pneumonia*
`Skin infection*
`Epistaxis
`Cough
`Dizziness
`Headache
`Skin cancer*
`
`21
`13
`19
`19
`14
`14
`19
`13
`14
`13
`11
`
`Grade 3 or 4
`(%)
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`6
`2
`0
`0
`0
`0
`0
`
`14
`
`

`

`
`
`
`
`Table 10: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with WM (N=63)
`Percent of Patients (N=63)
`All Grades (%)
`Grade 3 or 4 (%)
`43
`13
`44
`19
`13
`8
`
`Platelets Decreased
`Neutrophils Decreased
`Hemoglobin Decreased
`* Based on laboratory measurements.
`
`Additional Important Adverse Reactions
`Diarrhea
`Diarrhea of any grade occurred at a rate of 43% (range, 36% to 63%) of patients treated with
`IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 15%) and Grade 3 in 3% (range,
`0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade
`diarrhea was 12 days (range, 0 to 627), of Grade 2 was 37 days (range, 1 to 667) and of Grade 3
`was 71days (range, 3 to 627). Of the patients who reported diarrhea, 83% had complete
`resolution, 1% had partial improvement and 16% had no reported improvement at time of
`analysis. The median time from onset to resolution or improvement of any grade diarrhea was
`5 days (range, 1 to 418), and was similar for Grades 2 and 3. Less than 1% of patients
`discontinued IMBRUVICA due to diarrhea.
`Visual Disturbance
`Blurred vision and decreased visual acuity of any grade occurred in 10% of patients treated with
`IMBRUVICA (9% Grade 1, 2% Grade 2). The median time to first onset was 88 days (range,
`1 to 414 days). Of the patients with visual disturbance, 64% had complete resolution and 36%
`had no reported improvement at time of analysis. The median time from onset to resolution or
`improvement was 29 days (range, 1 to 281 days).
`
`Postmarketing Experience
`6.2
`The following adverse reactions have been identified during post-approval use of IMBRUVICA.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`Hepatobiliary disorders: hepatic failure (includes multiple terms)
`Respiratory disorders: interstitial lung disease (includes multiple terms)
`Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions (5.7)]
`Skin and subcutaneous tissue disorders: anaphylactic shock, angioedema, urticaria
`
`
`Reference ID: 3952152
`
`15
`
`

`

`
`
`DRUG INTERACTIONS
`7
`CYP3A Inhibitors
`7.1
`Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A). In healthy
`volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and
`AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in
`clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose
`AUC values of 1445 ± 869 ng ⋅ hr/mL which is approximately 50% greater than steady state
`exposures seen at the highest indicated dose (560 mg).
`Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of
`CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for
`7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,
`telithromycin) consider interrupting IMBRUVICA therapy during the durat