`
`
`
`
`
`
`
` 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 (1.4)
`01/15
`
`
`
`
`
`Dosage and Administration (2.2, 2.3, 2.5)
`01/15
`
`
`
`
`
`01/15
`Warnings and Precautions (5.1, 5.6)
`
`----------------------------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) who have received at least one
`
`
`prior therapy (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
`
`
`
`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
`Second Primary Malignancies
`
`5.6
`Tumor Lysis Syndrome
`
`
`
`5.7
`Embryo-Fetal Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experiences
`
`
`Postmarketing Experience
`6.2
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`• Hemorrhage: Monitor for bleeding (5.1).
`
`
`
`
`
`
`• Infections: Monitor patients for fever and infections and evaluate promptly
`
`
`(5.2).
`
`• Cytopenias: Check complete blood counts monthly (5.3).
`
`
`
`• Atrial Fibrillation: Monitor patients for atrial fibrillation (5.4).
`
`
`
`
`• Second Primary Malignancies: Other malignancies have occurred in
`
`
`patients, including skin cancers, and other carcinomas (5.5).
`
`• Tumor Lysis Syndrome (TLS): Monitor patients at risk for TLS (e.g. high
`
`
`
`tumor burden) (5.6).
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`
`
`
`
`
`
`potential risk to a fetus and to avoid pregnancy while taking the drug (5.7).
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`The most common adverse reactions (≥25%) in patients with B-cell
`
`malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia,
`
`
`
`diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper
`
`
`
`respiratory tract infection, and rash.
`
`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: Avoid use of IMBRUVICA in patients with moderate or
`
`
`
`severe baseline hepatic impairment. In patients with mild impairment, reduce
`
`
`IMBRUVICA dose (8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`approved patient labeling.
`
`
`
`
`Revised: 01/2015
`
`
`
`
`7
`
`DRUG INTERACTIONS
`
`
`
`7.1
`CYP3A Inhibitors
`
`
`7.2
`CYP3A Inducers
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6
`Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`8.8
`Females and Males of Reproductive Potential
`
`
`
`8.9
`Plasmapheresis
`
`
`
`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.
`
`
`
`Reference ID: 3694103
`
`
`
` 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) who have received at least one prior therapy [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
`
`
`Dosing Guidelines
`2.1
`
`
`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.
`
`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, 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
`
`
`
`
`
`
`
` 2
`
`Reference ID: 3694103
`
`

`

`
` 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: 3694103
`
`
`
` 3
`
`

`

`
`4
`
` None
`
`
`
`
` CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`5
`
`
`
` 5.1 Hemorrhage
`
` Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher
`
`
` bleeding events (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.
` 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 26% of patients. [See Adverse Reactions (6.1)]. Cases of
`
`
`
` progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with
`
`
` IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.
`
`
`
`
` 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.
`
`
` 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, 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. If atrial fibrillation persists, consider the risks and benefits of
`
` IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3)].
`
`
`
`
`
` Second Primary Malignancies
` 5.5
`
`
`
`
` Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have
`
`
`
` occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy
`
`
`
`
`
`
` was non-melanoma skin cancer (range, 4 to 11 %).
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 4
`
`

`

`
` Tumor Lysis Syndrome
` 5.6
`
`
`
` Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely
` and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor
`
`
`
`burden).
`
`
`
` Embryo-Fetal Toxicity
` 5.7
`
`
`
`
` Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in
`patients with MCL and 20 times those reported in patients with CLL or WM, receiving the
`
`
`ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were
`
`
`observed at lower exposures. Advise women to avoid becoming pregnant while taking
`
`IMBRUVICA. 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)]
`
`
`
`
`• Second Primary Malignancies [see Warnings and Precautions (5.5)]
`
`
`
`
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
`
`
`
`
`
`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.
`
`
`
`Clinical Trials Experience
`6.1
`
`
`
`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).
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 5
`
`

`

`
`
` 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: 3694103
`
`
`
` 6
`
`

`

`
`
`
`
` Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`
` MCL (N=111)
`
`
`
`
` System Organ Class
` Preferred Term
`
`
`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
`
`
`
`
`
` 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
`
`
`General disorders and
`
`administrative site
`
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`
`Musculoskeletal and
`connective tissue disorders
`
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
`Metabolism and nutrition
`
`disorders
`
`
`Nervous system disorders
`
`Reference ID: 3694103
`
`
`
` 7
`
`

`

` 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
`
`
`
`
`
`
`
` 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 an open label clinical trial
`
`
`(Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial
`
`
`
`
`
`
`(Study 2) that included 391 randomized patients with previously treated CLL or SLL.
`
`
`
`
`The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were
`
`
`
`
`thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper
`
`
`
`
`respiratory tract infection, rash, nausea, and pyrexia.
`
`
`
`
`Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2
`
`
`
`
`discontinued treatment due to adverse events. These included infections, subdural hematomas
`
`
`and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% 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% are presented in Tables 3 and 4.
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 8
`
`

`

`
`
`
` Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
` CLL (N=48) in Study 1
`
`
`
`
`
`
`
` System Organ Class
`
`
`Gastrointestinal disorders
`
`
`Infections and infestations
`
`
`
`General disorders and
`
`
`administrative site conditions
`
`
`
`Skin and subcutaneous tissue
`
`disorders
`
`
`Respiratory, thoracic and
`
`mediastinal disorders
`
`Musculoskeletal and
`
`connective tissue disorders
`
`
`
`Nervous system disorders
`
`
`
` Preferred Term
`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: 3694103
`
`

`

`
`
` 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.
`
`
`
`
` Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` System Organ Class
`
`ADR Term
`
`Gastrointestinal disorders
`
`Diarrhea
`
`Nausea
`
`Stomatitis*
`
`Constipation
`
`Vomiting
`General disorders and
`
`
`administration site conditions
`
`
`Fatigue
`
`Pyrexia
`
`Infections and infestations
`Upper respiratory tract
`
`
`infection
`
`Pneumonia*
`
`Sinusitis*
`
` Urinary tract infection
`
`Skin and subcutaneous tissue
`
`
`
`disorders
`
`Rash*
`
`Petechiae
`
`Bruising*
`
`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
`
`
`
`
`28
`
`24
`
`
`16
`
`
`15
`
`11
`
`10
`
`
`
`24
`
`14
`
`12
`
`
`2
`
`2
`
`
`1
`
`
`10
`
`1
`
`4
`
`
`
`3
`
`0
`
`0
`
`
`30
`
`15
`
`
`11
`
`
`13
`
`6
`
`5
`
`
`
`13
`
`1
`
`1
`
`
`2
`
`1
`
`
`2
`
`
`9
`
`0
`
`1
`
`
`
`0
`
`0
`
`0
`
`
`
` 10
`
`Reference ID: 3694103
`
`

`

`
`
`
`
` System Organ Class
`
`ADR Term
`Musculoskeletal and
`
`connective tissue disorders
`
`Musculoskeletal Pain*
`
`Arthralgia
`
`Nervous system disorders
`
`Headache
`
`Dizziness
`Injury, poisoning and
`
`
`procedural complications
`
`Contusion
`
`Eye disorders
`
`Vision blurred
`
`IMBRUVICA
`
`
`(N=195)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`Ofatumumab
`
`
`(N=191)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`
`28
`
`17
`
`
`14
`
`11
`
`
`
`11
`
`
`10
`
`
`2
`
`1
`
`
`1
`
`0
`
`
`
`0
`
`
`0
`
`
`18
`
`7
`
`
`6
`
`5
`
`
`
`3
`
`
`3
`
`
`1
`
`0
`
`
`0
`
`0
`
`
`
`0
`
`
`0
`
` 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
`
`
`
`
`
`
`
`
`
`
`Ofatumumab
`
`(N=191)
`
`Grade 3 or 4
`All Grades
`
`
`(%)
`(%)
`
`
`
`
` 57
` 26
`
` 45
`
` 10
`
` 21
`
` 0
`
`
`
`
`
` 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
`
`
` 52
`
` 5
` Platelets Decreased
` Hemoglobin Decreased
`
` 36
`
` 0
`
`
` * Based on laboratory measurements per IWCLL criteria
`
` 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 7 and 8 reflect
`
`
`
`
`
`
` exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 11
`
`

`

`
`
`
`
` Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`
` Waldenström’s Macroglobulinemia (N=63)
`
`
`
`
`
`
` Preferred Term
`
` Diarrhea
`
` Nausea
` Stomatitis*
`
` Gastroesophageal reflux disease
`
` Rash*
`Bruising*
`
`Pruritus
`
` Fatigue
`
`
`
`
`
`
`
`
`
` All Grades
`
` (%)
`
` 37
`
` 21
`
` 16
`
` 13
`
` 22
`
` 16
`
` 11
`
` 21
`
`
` Grade 3 or 4
`
` (%)
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
`
` System Organ Class
`
` 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
`
`
`
`
`
`
`
`
`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
`
`
` 0
`
` 0
`
` 0
`
` 0
`
` 6
`
` 2
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
` Neoplasms benign,
`
` malignant, and unspecified
`
` (including cysts and polyps)
`
` The system organ class and individual ADR terms are sorted in descending frequency order.
`
`
`
` * Includes multiple ADR terms.
`
`
`
`
`Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
`
`
`
`in Patients with WM (N=63)
`
`
`
`
`
`
` Platelets Decreased
`
`
` Neutrophils Decreased
`
`
`Hemoglobin Decreased
`
` * Based on laboratory measurements.
`
`
`
`
`
`
`Percent of Patients (N=63)
`
`
`
` Grade 3 or 4 (%)
`All Grades (%)
`
`
`43
`13
`
`
`44
`19
`
`
`13
`8
`
` 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
`
`
`
`
` 12
`
`Reference ID: 3694103
`
`

`

`
` always possible to reliably estimate their frequency or establish a causal relationship to drug
`
` exposure.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have
`been reported.
`
`
`
`
`
`
`DRUG INTERACTIONS
`7
`
`
`Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.
`
`
`
`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 (2.4), and Clinical Pharmacology (12.3)].
`
`
`
`
` CYP3A Inducers
` 7.2
`
`
` Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib
`
` Cmax and AUC by approximately 13- and 10-fold, respectively.
`
`
`
`
`
` Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and
`
`St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical
`
` Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`8
` USE IN SPECIFIC POPULATIONS
`
` 8.1
`
`
` Pregnancy
` Pregnancy Category D [see Warnings and Precautions (5.7)].
`
`
` Risk Summary
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 13
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`
` pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant
`
` while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.
`
`
`
`
` Animal Data
`
` Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral
` doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with
`
`
`
`
` visceral malformations (heart and major vessels) and increased post-implantation loss. The dose
` of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL
`
`
`
`
`
` and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily
` and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with
`
`
`
`
`
` decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the
`
`
` exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
`
`
`
`
` 8.3
` Nursing Mothers
` It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in
`
`
`
`
`
` human milk and because of the potential for serious adverse reactions in nursing infants from
` IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the
`
`
` drug, taking into account the importance of the drug to the mother.
`
`
` 8.4
` Pediatric Use
` The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.
`
`
`
` 8.5 Geriatric Use
` Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences
`
`
`
` in effectiveness were observed between these patients and younger patients. Cardiac adverse
`events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and
`
`
` gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly
`
` patients.
`
`
`
`
`
`
` Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences
`
` in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred
`
`
`
`
` more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65
`
`
`
`
`
` versus 51% of younger patients) [see Clinical Studies (14.2)].
`
`
`
`
`
`
` Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in
`
`
`
`
` effectiveness were observed between these patients and younger patients. Cardiac adverse events
`
`
` (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection)
`
`
` occurred more frequently among elderly patients.
`
`
`
`
` 8.6
` Renal Impairment
`Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with
`
` Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal
` impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 14
`
`

`

`
` 8.7 Hepatic Impairment
`
`
`
`
` Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in
` ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-,
`
`
`
`
` 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and
` severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function.
`
`
`
`
`
` The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment.
`
` Moni