`
`
`
`
`
`
`
` 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)
`3/2016
`
`
`
`
`
`Warnings and Precautions (5.5)
`3/2016
`
`
`
`
`
`
`Overdosage (10)
`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) (1.2).
`
`
`
`
`• Chronic lymphocytic leukemia 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 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
`
`
`Chronic Lymphocytic Leukemia
`1.2
`
`
`
`
`1.3
`Chronic Lymphocytic Leukemia 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
`
`
`Postmarketing Experience
`6.2
`
`
`
`Reference ID: 3896712
`
`
`
`
`• 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, WM) were thrombocytopenia, diarrhea, anemia,
`
`
`
`
`
`
`neutropenia, musculoskeletal pain, fatigue, bruising, nausea, rash, and upper
`
`
`
`respiratory tract infection (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 d ose (2.4, 7.1).
`
`
`
`• CYP3A Inducers: Avoid co-administration with strong CYP3A inducers
`
`
`(7.2).
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`
`
`Hepatic Impairment: Avoid use of IMBRUVICA in patients with moderate or
`
`
`
`severe baseline hepatic impairment. In patients with mild impairment, reduce
`
`
`
`IMBRUVICA d ose (2.5, 8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`approved patient labeling.
`
`
`
`
`
`
`Revised: 3/2016
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`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
`
`
`Pediatric Use
`8.4
`
`
`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
`
`
`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
`1
`
` INDICATIONS AND USAGE
`
` 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)].
`
`
`
`Chronic Lymphocytic Leukemia
`1.2
`
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`
`
`(CLL) [see Clinical Studies (14.2)].
`
`
`Chronic Lymphocytic Leukemia with 17p deletion
`1.3
`
`
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`
`
`(CLL) 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.
`
`
`Dosage
`2.2
`
`Mantle Cell Lymphoma
`
`The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once
`
`
`daily.
`
`Chronic Lymphocytic Leukemia and Waldenström’s Macroglobulinemia
`
`
`The recommended dose of IMBRUVICA for CLL and WM is 420 mg (three 140 mg capsules)
`
`
`
`
`orally once daily.
`
`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
`
`
`
`
`Reference ID: 3896712
`
`
`
` 2
`
`

`

`
` (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 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 (8.7) 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 capsules of
` IMBRUVICA should not be taken to make up for the missed dose.
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`3
`
`
` 140 mg capsules
`
`
`
`Reference ID: 3896712
`
`
`
` 3
`
`

`

`
`4
`
` None
`
`
`
`
` CONTRAINDICATIONS
`
`
`
`5
` WARNINGS AND PRECAUTIONS
`
` 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)].
`
`
`
`Infections
`5.2
`
`Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater
`
`
`
`
`infections occurred in 14% to 26% 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.
`
`Cytopenias
`5.3
`
`Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%),
`
`thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated
`
`
`
`
`
`with IMBRUVICA.
`
`Monitor complete blood counts monthly.
`Atrial Fibrillation
`5.4
`
`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,
`
`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
`
`
`
`
`
`
`dose modification [see Dosage and Administration (2.3)].
`
`
`
`
`
`Reference ID: 3896712
`
`
`
` 4
`
`

`

`
`
` 5.5 Hypertension
`
`
`
` Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a
`
`
` median time to onset of 4.5 months (range, 0.03 to 18.40 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.
`
`Second Primary Malignancies
`5.6
`
`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%).
`
`
`
`Tumor Lysis Syndrome
`5.7
`
`Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the
`
`
`baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely
`
`and treat as appropriate.
`
`
`Embryo-Fetal Toxicity
`5.8
`
`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 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)]
`
`
`
`
`• Second Primary Malignancies [see Warnings and Precautions (5.6)]
`
`
`
`
`
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`Reference ID: 3896712
`
`
`
` 5
`
`

`

`
`
` 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.
`
`
`Reference ID: 3896712
`
`
`
` 6
`
`

`

`
`
`
`
` Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`MCL (N=111)
`
`
`
`
`
`
`
`
`
`
`
`
` General disorders and
`
`administration site
`
`conditions
`
`
`
` Skin and subcutaneous
`
` tissue disorders
`
`
`
`Musculoskeletal and
` connective tissue disorders
`
`
`
`
`
` Respiratory, thoracic and
`
` mediastinal 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
`
` 11
`
` 21
`
` 12
`
` 14
`
` 13
`
` 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
`
` 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
`
`
`
` 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)
`
`
`
` Grade 3 or 4 (%)
`All Grades (%)
`
`
`57
`17
`
`
`47
`29
`
`
`41
`9
`
`Reference ID: 3896712
`
`
`
` 7
`
`

`

`
`
`
`
`
` 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
`
`
`The data described below reflect exposure to IMBRUVICA in one single arm, open-label clinical
`
`
`
`trial and two randomized controlled clinical trials in patients with CLL/SLL. Study 1 included 48
`
`patients with previously treated CLL, Study 2 included 391 randomized patients with previously
`
`treated CLL or SLL who received single agent ibrutinib or ofatumumab, and Study 3 included
`
`269 randomized patients 65 years or older with treatment naïve CLL or SLL who received single
`
`agent ibrutinib or chlorambucil.
`The most commonly occurring adverse reactions in Studies 1, 2, and 3 in patients with CLL/SLL
`
`
`receiving IMBRUVICA (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia,
`
`
`
`
`musculoskeletal pain, fatigue, bruising, nausea, rash, pyrexia and cough. Four to ten percent of
`
`
`patients receiving IMBRUVICA in Studies 1, 2, and 3 discontinued treatment due to adverse
`
`
`
`reactions. These included pneumonia, subdural hematomas and atrial fibrillation
`
`(1% each). Adverse reactions leading to dose reduction occurred in approximately 4% of
`
`
`patients.
`
`Study 1
`
`Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent
`
`
`
`
`
`IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% with a median duration of treatment of
`
`
`
`
`
`15.6 months are presented in Tables 3 and 4.
`
`
`
`
`Reference ID: 3896712
`
`
`
` 8
`
`

`

`
`
`
` Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
` CLL (N=48) 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
`
`Peripheral neuropathy
`
`Decreased appetite
`
`
`Second malignancies*
`
`
`Laceration
`
`
`Metabolism and nutrition
`
`disorders
`
`Neoplasms benign,
`
`malignant, unspecified
`
`Injury, poisoning and
`
`procedural complications
`
`Psychiatric disorders
`
`
`Anxiety
`
`Insomnia
` Hypertension
`
` Vascular disorders
`
`
` *One patient death due to histiocytic sarcoma.
`
`
`
` All Grades (%)
`63
`23
`21
`21
`19
`15
`13
`48
`21
`17
`10
`10
`31
`25
`23
`13
`13
`54
`27
`17
`19
`15
`10
`27
`23
`19
`21
`19
`10
`17
`
`10*
`
`10
`
`10
`10
`
` 17
`
`
` Grade 3 or 4
`
` (%)
`4
`2
`2
`0
`2
`0
`0
`2
`6
`6
`8
`0
`4
`2
`0
`4
`0
`2
`0
`0
`0
`0
`0
`6
`0
`2
`0
`2
`0
`2
`
`0
`
`2
`
`0
`0
`
` 8
`
`
`
` 9
`
`Reference ID: 3896712
`
`

`

`
`
` Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
`
`
`
`
`
`
` in Patients with CLL (N=48) in Study 1
`
`
`
`
`
`
`
`
`
`
`
` Percent of Patients (N=48)
`
`
`Grade 3 or 4 (%)
`All Grades (%)
`
`
`
`
`
`71
`10
`Platelets Decreased
`
`
`
`54
`27
` Neutrophils Decreased
`
`
`
`
`44
`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.
`
`
`
`
`Reference ID: 3896712
`
`
`
` 10
`
`

`

`
` Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`
`
`
`
`
` IMBRUVICA Treated Arm in Patients in Study 2
`
`
`
`
`
`
`IMBRUVICA
`
`
`(N=195)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`
`48
`4
`
`
`26
`2
`
`
`17
`1
`
`
`15
`0
`
`
`14
`0
`
`
`
`Ofatumumab
`
`
`(N=191)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`
`18
`2
`
`
`18
`0
`
`
`6
`1
`
`
`9
`0
`
`
`6
`1
`
`
`
`
`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*
`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
`
`
`24
`
`
`16
`
`
`15
`
`11
`
`10
`
`
`
`24
`
`14
`
`12
`
`
`
`28
`
`17
`
`
`14
`
`11
`
`
`
`2
`
`
`1
`
`
`10
`
`1
`
`4
`
`
`
`3
`
`0
`
`0
`
`
`
`2
`
`1
`
`
`1
`
`0
`
`
`
`15
`
`
`11
`
`
`13
`
`6
`
`5
`
`
`
`13
`
`1
`
`1
`
`
`
`18
`
`7
`
`
`6
`
`5
`
`
`
`3
`
`
`3
`
`
`1
`
`
`2
`
`
`9
`
`0
`
`1
`
`
`
`0
`
`0
`
`0
`
`
`
`1
`
`0
`
`
`0
`
`0
`
`
`
`0
`
`
`0
`
`
`
`Reference ID: 3896712
`
`
`
` 11
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
` in Study 2
`
`
`
`
` IMBRUVICA
`
` (N=195)
`
` Grade 3 or 4
`
` All Grades
`
`
` (%)
` (%)
`
` Neutrophils Decreased
`51
`23
`Platelets Decreased
`52
`5
`
` Hemoglobin Decreased
`
`
`
` 36
` 0
`
` * Based on laboratory measurements per IWCLL criteria.
`
`
` Ofatumumab
`
` (N=191)
`
` Grade 3 or 4
`
` All Grades
`
`
` (%)
` (%)
`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: 3896712
`
`
`
` 12
`
`

`

`
`
`
`
`
`
`
`
`
` 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
`
` Grade 3 or 4
`
` All Grades
`
` Grade 3 or 4
`
` All Grades
`
`
`
`
`
`Adverse Reaction
`(%)
`(%)
`(%)
`(%)
`
`
`
`
`
`Gastrointestinal disorders
`
`
`
`
`
`
`Diarrhea
`42
`4
`17
`0
`
`
`
`
`
`
`Stomatitis*
`14
`1
`1
`4
`Musculoskeletal and
`
`
`
`
`
`connective tissue disorders
`
`
`
`
`
`36
`4
`
`Musculoskeletal pain*
`20
`0
`
`
`
`
`
`1
`16
`
`Arthralgia
`1
`7
`
`
`
`
`
`0
`11
`
`Muscle spasms
`5
`0
`
`
`
`
`
`Eye Disorders
`
`
`
`
`
`0
`17
`
`Dry eye
`5
`0
`
`
`
`
`
`0
`13
`
`
` Lacrimation increased
`6
`0
`
`
`
`
`
`0
`13
`Vision blurred
`
`8
`0
`
`
`
`
`
`0
`11
`
`Visual acuity reduced
`2
`0
` Skin and subcutaneous tissue
`
`
`
`
`
`
`
`disorders
`
`
`
`
`
`4
`21
`Rash*
`
`12
`2
`
`
`
`
`
`0
`19
`
`Bruising*
`0
`7
`
`
`
`
`
`Infections and infestations
`
`
`
`
`
`2
`15
` Skin infection*
`3
`1
`
`
`
`
`
`8
`14
`
`Pneumonia*
`7
`4
`
`
`
`
`
`1
`10
`
`Urinary tract infections
`8
`1
`
` Respiratory, thoracic and
`
`
`
`
`
`mediastinal disorders
`
`
`
`
`
`0
`22
`
`Cough
`15
`0
`
` General disorders and
`
`
`
`
`
` administration site conditions
`
`
`
`
`
`
`1
`19
`Peripheral edema
`
`9
`0
`
`
`
`
`
`0
`17
`
`Pyrexia
`14
`2
`
`
`
`
`
`Vascular Disorders
`
`
`
`
`4
`14
` Hypertension*
`1
`0
`
`
`
`
`
`Nervous System Disorders
`
`
`
`
`
`1
`12
`
`Headache
`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: 3896712
`
`
`
` 13
`
`

`

`
` 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 8 and 9 reflect
`
`
`
` exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.
`
`
`
`
`
`
` Table 8: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`
`Waldenström’s Macroglobulinemia (N=63)
`
`All Grades
`
` (%)
`
` 37
`21
`16
`13
`
` 22
`16
`11
`
` 21
`
`
`
`
`
`
`
` Adverse Reaction
`
` Diarrhea
`
` Nausea
` Stomatitis*
`
` Gastroesophageal reflux disease
`
` Rash*
`Bruising*
`
`Pruritus
`
` Fatigue
`
` 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
`
`
`
`
`
` Grade 3 or 4
`
` (%)
`
` 0
`0
`0
`0
`
` 0
`0
`0
`
` 0
`
` 0
`
`0
`
` 0
`0
`6
`2
`
` 0
`0
`
` 0
`
` 0
`0
`
`
`
` 14
`
`
`
`
`
`
`
`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
`
`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: 3896712
`
`

`

`
`
`
`
`
` Platelets Decreased
`
`
`Neutrophils Decreased
`
`
`Hemoglobin Decreased
` * Based on laboratory measurements.
`
`
`
`
` Table 9: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
`
`
`
` in Patients with WM (N=63)
`
`
` Percent of Patients (N=63)
`
`
`
`
` Grade 3 or 4 (%)
`All Grades (%)
`
`
`43
`13
`
`
`44
`19
`
`
`13
`8
`
`
`
`
`
`
`
` Additional Important Adverse Reactions
`Diarrhea
`Diarrhea of any grade occurred at a rate of 47% (range, 37% to 63%) of patients treated with
`
`
`
`
`
`IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 15%) and Grade 3 in 4% (range,
`
`
`
`0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade
`
`
`
`diarrhea was 8 days (range, 0 to 627), of Grade 2 was 28 days (range, 1 to 540) and of Grade 3
`
`was 77 days (range, 3 to 627). Of the patients who reported diarrhea, 83% had complete
`
`
`resolution, 2% had partial improvement and 15% 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 408), 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 11% of patients treated with
`
`
`
`
`IMBRUVICA (10% Grade 1, 1% Grade 2). The median time to first onset was 92 days (range,
`
`1 to 414 days). Of the patients with visual disturbance, 58% had complete resolution and 42%
`
`had no reported improvement at time of analysis. The median time from onset to resolution or
`
`
`improvement was 29 days (range, 1 to 202 days).
`
`
`6.2
`Postmarketing Experience
`
`The following adverse reactions have been identified during post-approval use of IMBRUVICA.
`
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`
`
`
`
`exposure.
`Hypersensitivity reactions i ncluding anaphylactic s hock ( fatal), u rticaria, and an gioedema h ave
`
`
`
`
`been reported. Severe liver toxicities, such as hepatic failure, have also been reported.
`
`
`
`
`
`DRUG INTERACTIONS
`7
`
`
`Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A).
`
`
`
`
`Reference ID: 3896712
`
`
`
` 15
`
`

`

`
` CYP3A Inhibitors
`7.1
`
` 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 duration of inhibitor use.
`
`
`Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must
`
`
`be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate
`
`
`
`CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see
`
`
`
`Dosage and Administration (2.4)].
`
`Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate
`
`
`inhibitors of CYP3A [see Dosage and Administration