HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` IMBRUVICA safely and effectively. See full prescribing information for
`
`
` IMBRUVICA.
`IMBRUVICA® (ibrutinib) capsules, for oral use
`
`
`
`
`
`
`IMBRUVICA® (ibrutinib) tablets, for oral use
`
`
`
`IMBRUVICA® (ibrutinib) oral suspension
`
`Initial U.S. Approval: 2013
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`
`
`Indications and Usage, cGVHD (1.6)
`8/2022
`
`
`
`Dosage and Administration (2.1, 2.3, 2.4)
`8/2022
`
`
`
`Dosage and Administration (2.2)
`5/2022
`
`
`Warnings and Precautions,
`
`Cardiac Arrhythmias, Cardiac Failure, and Sudden Death (5.3)
`
`Hypertension (5.4)
`
`
`5/2022
`
`5/2022
`
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`
`
`
`IMBRUVICA is a kinase inhibitor indicated for the treatment of:
`
`
`
`
`
`• Adult patients with mantle cell lymphoma (MCL) who have received at
`
`
`
`least one prior therapy (1.1).
`
`
`
`
`
`This indication is approved under accelerated approval based on overall
`
`
`
`
`response rate. Continued approval for this indication may be contingent
`
`
`
`
`upon verification and description of clinical benefit in a confirmatory
`
`trial(s).
`
`
`
`• Adult patients with chronic lymphocytic leukemia (CLL)/Small
`
`
`lymphocytic lymphoma (SLL) (1.2).
`
`
`
`• Adult patients with chronic lymphocytic leukemia (CLL)/Small
`
`
`lymphocytic lymphoma (SLL) with 17p deletion (1.3).
`
`
`• Adult patients with Waldenström’s macroglobulinemia (WM) (1.4).
`
`
`
`
`
`• Adult patients with marginal zone lymphoma (MZL) who require
`
`
`
`
`
`systemic therapy and have received at least one prior anti-CD20-based
`
`therapy (1.5).
`
`
`
`
`
`This indication is approved under accelerated approval based on overall
`
`
`
`
`response rate. Continued approval for this indication may be contingent
`
`
`
`
`upon verification and description of clinical benefit in a confirmatory
`
`trial(s).
`
`
`
`
`
`
`
`
`• Adult and pediatric patients age 1 year and older with chronic graft versus
`
`
`host disease (cGVHD) after failure of one or more lines of systemic
`
`therapy (1.6).
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
`• MCL and MZL: 560 mg taken orally once daily (2.1).
`
`
`
`
`
`
`• CLL/SLL and WM: 420 mg taken orally once daily (2.1).
`
`
`cGVHD:
`•
`
`
`
`
`
`
`
`o Patients 12 years and older: 420 mg taken orally once daily (2.1).
`
`
`
`
`
`
`o Patients 1 to less than 12 years of age: 240 mg/m2 taken orally once
`
`
`daily (up to a dose of 420 mg) (2.1).
`
`
`
`
`
`
`Tablets or capsules should be taken orally with a glass of water. Do not open,
`
`
`
`break, or chew the capsules. Do not cut, crush, or chew the tablets. See full
`
`
`
`
`prescribing information for oral suspension administration instructions (2.1).
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Mantle Cell Lymphoma
`
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic
`1.2
`
`
`
`Lymphoma
`
`1.3
`Chronic Lymphocytic Leukemia/Small Lymphocytic
`
`
`
`Lymphoma with 17p deletion
`
`
`
`1.4 Waldenström’s Macroglobulinemia
`
`
`1.5 Marginal Zone Lymphoma
`
`
`
`1.6
`Chronic Graft versus Host Disease
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1
`Recommended Dosage
`
`
`2.2 Dosage Modifications for Adverse Reactions
`
`
`
`
`2.3 Dosage Modifications for Use with CYP3A Inhibitors
`
`
`
`2.4 Dosage Modifications for Use in Hepatic Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hemorrhage
`
`
`5.2
`Infections
`
`5.3
`Cardiac Arrhythmias, Cardiac Failure, and Sudden
`
`
`Death
`
`
`5.4 Hypertension
`
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`Capsules: 70 mg and 140 mg (3)
`
`
`
`
`
`Tablets: 140 mg, 280 mg, 420 mg, and 560 mg (3)
`
`Oral suspension: 70 mg/mL (3)
`
`------------------------------CONTRAINDICATIONS------------------------------
`
`None (4)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
`• Hemorrhage: Monitor for bleeding and manage (5.1).
`
`
`
`
`
`
`• Infections: Monitor patients for fever and infections, evaluate promptly,
`
`
`and treat (5.2).
`
`
`• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Monitor for
`
`
`
`
`
`symptoms of arrhythmias and cardiac failure and manage (5.3).
`
`
`
`
`
`• Hypertension: Monitor blood pressure and treat (5.4).
`
`
`
`• Cytopenias: Check complete blood counts monthly (5.5).
`
`
`
`
`• Second Primary Malignancies: Other malignancies have occurred in
`
`
`
`patients, including skin cancers, and other carcinomas (5.6).
`
`• Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
`
`
`Monitor and treat for TLS (5.7).
`
`
`
`
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`
`
`
`
`
`
`
`reproductive potential of the potential risk to a fetus and to use effective
`
`
`
`contraception (5.8, 8.1, 8.3).
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`
`
`
`
`
`• The most common (≥30%) adverse reactions in patients with B-cell
`
`
`malignancies (MCL, CLL/SLL, WM and MZL) are thrombocytopenia,
`
`diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and
`
`bruising (6).
`
`
`
`
`
`
`• The most common (≥20%) adverse reactions in adult or pediatric patients
`
`
`with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia,
`
`
`
`musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage,
`
`
`
`nausea, abdominal pain, pneumonia, and headache (6).
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`
`
`
`
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`-------------------------------DRUG INTERACTIONS------------------------------
`
`
`
`
`• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1).
`
`
`
`
`
`• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
`
`(7.2).
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`
`• Lactation: Advise not to breastfeed. (8.2)
`
`
`
`
`
`• Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe
`
`
`
`hepatic impairment. In patients with mild or moderate impairment, reduce
`
`
`IMBRUVICA dose (2.4, 8.6).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`approved patient labeling.
`
`
`
`
`
`
`Revised: 8/2022
`
`
`
`
`7
`
`
`
`Cytopenias
`5.5
`
`
`Second Primary Malignancies
`5.6
`
`
`Tumor Lysis Syndrome
`5.7
`
`
`Embryo-Fetal Toxicity
`5.8
`
`
`6 ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`
`Postmarketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`
`7.1
`Effect of CYP3A Inhibitors on Ibrutinib
`
`
`
`
`Effect of CYP3A Inducers on Ibrutinib
`7.2
`
`
`
`
`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
`
`Reference ID: 5035070
`
`
`
` 1
`
`

`

`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Mantle Cell Lymphoma
`
`
`14.2 Chronic Lymphocytic Leukemia / Small Lymphocytic
`
`
`
`
`Lymphoma
`
`
`14.3 Waldenström’s Macroglobulinemia
`
`
`
`
` 14.4 Marginal Zone Lymphoma
`
`
`14.5 Chronic Graft versus Host Disease
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
`
`PATIENT COUNSELING INFORMATION
`17
`* Sections or subsections omitted from the full prescribing information are
`
`
`
`
`
`
`not listed.
`
`
`Reference ID: 5035070
`
`
`2
`
`

`

`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1
` INDICATIONS AND USAGE
` 1.1 Mantle Cell Lymphoma
`
` IMBRUVICA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL)
`
` who have received at least one prior therapy.
`This indication is approved under accelerated approval based on overall response rate. Continued
`approval for this indication may be contingent upon verification and description of clinical
`
`benefit in a confirmatory trial(s) [see Clinical Studies (14.1)].
`
`
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`1.2
`
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`
`(CLL)/small lymphocytic lymphoma (SLL).
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
`1.3
`
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
`
`1.4 Waldenström’s Macroglobulinemia
`
`IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
`
`macroglobulinemia (WM).
`1.5 Marginal Zone Lymphoma
`
`IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma
`
`(MZL) who require systemic therapy and have received at least one prior anti-CD20-based
`
`therapy.
`
`This indication is approved under accelerated approval based on overall response rate [see
`
`
`Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon
`verification and description of clinical benefit in a confirmatory trial(s).
`
`Chronic Graft versus Host Disease
`1.6
`
`IMBRUVICA is indicated for the treatment of adult and pediatric patients age 1 year and older
`
`
`
`with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic
`therapy.
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1
`Recommended Dosage
`
`Mantle Cell Lymphoma and Marginal Zone Lymphoma
`
`
`The recommended dosage of IMBRUVICA for MCL and MZL is 560 mg orally once daily until
`
`
`disease progression or unacceptable toxicity.
`
`Reference ID: 5035070
`
`
`3
`
`

`

`
`
`
`
`
`
`
` Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
`
` Macroglobulinemia
` The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily
`
`
`until disease progression or unacceptable toxicity.
` For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with
`
`
`rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).
`For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
`
`
`
`When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider
`
`administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
`
`Chronic Graft versus Host Disease
`
`The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is
`
`
`420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240
`
`mg/m2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an
`
`
`underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for
`
`the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical
`
`assessment of the individual patient.
` Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than
`
` 12 years of age using either IMBRUVICA capsules/tablets or oral suspension
`
`
` Recommended dose to achieve 240 mg/m2
`
`
`Volume (mL) of IMBRUVICA Oral
`Dose (mg) of IMBRUVICA
`
`
`Suspension (70 mg/mL) to Administer
`Capsules/Tablets to Administer
`
`
`
`
`
`BSA* (m2)
`
`Range
`> 0.3 to 0.4
`
`> 0.4 to 0.5
`
`> 0.5 to 0.6
`
`> 0.6 to 0.7
`
`> 0.7 to 0.8
`
`> 0.8 to 0.9
`
`> 0.9 to 1.0
`
`> 1.0 to 1.1
`
`> 1.1 to 1.2
`
`> 1.2 to 1.3
`
`> 1.3 to 1.4
`
`> 1.4 to 1.5
`
`> 1.5 to 1.6
`
`
`-
`
`-
`
`-
`
`-
`
`210 mg
`
`210 mg
`
`210 mg
`
`280 mg
`
`280 mg
`
`280 mg
`
`350 mg
`
`350 mg
`
`350 mg
`
`
`1.2 mL
`
`1.5 mL
`
`1.9 mL
`
`2.2 mL
`
`2.6 mL
`
`2.9 mL
`
`3.3 mL
`
`3.6 mL
`
`4 mL
`
`4.3 mL
`
`4.6 mL
`
`5 mL
`
`5.3 mL
`
`
`Reference ID: 5035070
`
`
`4
`
`

`

`
`
`Recommended dose to achieve 240 mg/m2
`
`
` Volume (mL) of IMBRUVICA Oral
` Dose (mg) of IMBRUVICA
`
`
`
`Capsules/Tablets to Administer
` Suspension (70 mg/mL) to Administer
`
`
`
`
`
`420 mg
`
`
`6 mL
`
`
`BSA* (m2)
`
`Range
`
`> 1.6
`
`*BSA = body surface area.
`
`
` Administration
` Administer IMBRUVICA at approximately the same time each day.
`
`
` Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the
`capsules. Do not cut, crush, or chew the tablets.
`Follow Instructions for Use for further administration details of IMBRUVICA oral suspension.
`If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
`
`
`on the same day with a return to the normal schedule the following day. Do not take extra doses
`
`
`of IMBRUVICA to make up for the missed dose.
`
`
`2.2
`Dosage Modifications for Adverse Reactions
`
`
`For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse
`
`
`reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage
`
`
`
`modifications (see Table 2).
`
`
`
`
`
`Adverse
`Reactiona,b
`
`
`
`Occurrence
`
`
`
`Table 2: Recommended Dosage Modifications for Adverse Reactions
`
`Dose Modification for
`
` Dose Modification
`Dose Modification for
`
`
`
`
`CLL/SLL, WM, and
` for MCL and
` Patients 1 Year to less
`
`
` than 12 Years with
` MZL After
`Patients 12 Years or
`
`
`older with cGVHD
`cGVHD After
`
` Recovery
`
` After Recovery
`Recovery
`
` Starting Dose =
`560 mg
`Starting Dose = 420 mg
`Starting Dose = 240
`
`
`mg/m2
`
`Restart at 280 mg dailyc Restart at 160 mg/m2
`
`
`
`
`dailyc
`
`
`
` Restart at 140 mg dailyc Restart at 80 mg/m2
`
`dailyc
`
`
`
`
`
`
`First
`
`
`Restart at 420 mg
`
`dailyc
`
`Grade 2 cardiac
`
`failure
`
`
`Second
`
`
`Third
`
`
`
` First
`
`Grade 3 cardiac
`arrhythmias
`
`
`
`Restart at 280 mg
`dailyc
`
`
`
`Discontinue
`
`IMBRUVICA
` Restart at 420 mg
`
` dailyc
`
`
`
`
`
`Discontinue
`Discontinue
`
`
`IMBRUVICA
`IMBRUVICA
` Restart at 280 mg dailyc Restart at 160 mg/m2
`
` dailyc
`
`
`
`
`
`
`
`Reference ID: 5035070
`
`
`5
`
`

`

`
`
`Adverse
`Reactiona,b
`
`
`
`Occurrence
`
`
`Dose Modification
`
`for MCL and
`
`MZL After
`
`Recovery
`
`Starting Dose =
`560 mg
`
`
`Dose Modification for
`
`CLL/SLL, WM, and
`
`
`Patients 12 Years or
`older with cGVHD
`
`After Recovery
`Starting Dose = 420 mg
`
`
`
`Second
`
` Discontinue
`
` IMBRUVICA
`
`
`
` Discontinue
`
` IMBRUVICA
`
`
`
`Dose Modification for
`Patients 1 Year to less
`
`
`than 12 Years with
`
`cGVHD After
`Recovery
`
`Starting Dose = 240
`mg/m2
`
`
` Discontinue
` IMBRUVICA
`
`
`
`Grade 3 or 4
`
`cardiac failure
`Grade 4 cardiac
`
`arrhythmias
`
`
`First
`
`
`Discontinue
`
`IMBRUVICA
`
`
`Discontinue
`
`IMBRUVICA
`
`
`Discontinue
`
`IMBRUVICA
`
`
`
` First
`
`
`
` Restart at 420 mg
`
` daily
`
`
`
` Restart at 280 mg daily
`
`
`
`
`
` Restart at 160 mg/m2
`dailyc
`
`
`
`Other Grade 3 or 4
`
`non-hematological
`toxicitiesd
`
`Grade 3 or 4
`neutropenia with
`infection or fever
`
`Grade 4
`hematological
`
` toxicities
`
` a [see Warnings and Precautions (5)].
`
`
`b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or
`
`International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
`
`
` c Evaluate the benefit-risk before resuming treatment.
`
`d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
`
`
`
` Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA
`
`
` capsules/tablets or oral suspension
`Recommended dose to achieve 160 mg/m2
`
`
`
`Recommended dose to achieve 80 mg/m2
`
`
` Dose (mg) of
`
`
`Volume (mL) of
` Dose (mg) of
`Volume (mL) of
`
`
`IMBRUVICA
`IMBRUVICA
`IMBRUVICA Oral
`IMBRUVICA Oral
`
`
`
`
`Capsules/Tablets to
`Suspension (70
`Capsules/Tablets to
`Suspension (70
`
`
`mg/mL) to
`mg/mL) to
`
`
`Administer
`Administer
`
`
`Administer
`Administer
`0.8 mL
`0.4 mL
`
`
`
`
`1 mL
`0.5 mL
`
`
`
`
`1.3 mL
`0.6 mL
`
`
`
`
`1.5 mL
`0.7 mL
`
`
`
`
`1.7 mL
`0.9 mL
`
`
`
`
`1.9 mL
`1 mL
`
`
`
`
`2.2 mL
`1.1 mL
`
`
`
`
`
`
`Second
`
`
`Third
`
`-
`
`-
`
`-
`
`-
`
`140 mg
`
`
`140 mg
`
`
`140 mg
`
`
`
`
`BSA* (m2)
`
`Range
`
`> 0.3 to 0.4
`
`> 0.4 to 0.5
`
`> 0.5 to 0.6
`
`> 0.6 to 0.7
`
`> 0.7 to 0.8
`
`> 0.8 to 0.9
`
`> 0.9 to 1.0
`
`
`
`Restart at 280 mg
`
`daily
`
`
`
`Restart at 140 mg daily
`
`
`Restart at 80 mg/m2
`
`dailyc
`
`
`Discontinue
`
`IMBRUVICA
`
`
`Discontinue
`
`IMBRUVICA
`
`
`Discontinue
`
`IMBRUVICA
`
`-
`
`-
`
`-
`
`-
`
`70 mg
`
`
`70 mg
`
`
`70 mg
`
`
`
`Reference ID: 5035070
`
`
`6
`
`

`

`
`
`
`BSA* (m2)
`
`Range
`
`Recommended dose to achieve 160 mg/m2
`
`
` Dose (mg) of
`
`
`Volume (mL) of
`
`IMBRUVICA
`IMBRUVICA Oral
`
`
`Capsules/Tablets to
`Suspension (70
`
`mg/mL) to
`
`Administer
`
`Administer
`2.4 mL
`
`
`2.6 mL
`
`
`2.9 mL
`
`
`3.1 mL
`
`
`3.3 mL
`
`
`3.5 mL
`
`
`4 mL
`
`
`
`
`Recommended dose to achieve 80 mg/m2
`
`
` Dose (mg) of
`Volume (mL) of
`
`IMBRUVICA
`IMBRUVICA Oral
`
`
`Capsules/Tablets to
`Suspension (70
`
`mg/mL) to
`
`Administer
`
`Administer
`1.2 mL
`
`
`1.3 mL
`
`
`1.4 mL
`
`
`1.5 mL
`
`
`1.7 mL
`
`
`1.8 mL
`
`
`2 mL
`
`
`
`70 mg
`
`
`-
`
`-
`
`-
`
`140 mg
`
`
`140 mg
`
`
`140 mg
`
`
`
`140 mg
`> 1.0 to 1.1
`
`
`
`210 mg
`> 1.1 to 1.2
`
`
`
`210 mg
`> 1.2 to 1.3
`
`
`
`210 mg
`> 1.3 to 1.4
`
`
`
`210 mg
`> 1.4 to 1.5
`
`
`
`280 mg
`> 1.5 to 1.6
`
`
`
`280 mg
`> 1.6
`
`
`
`
`*BSA = body surface area.
`
`
`Dosage Modifications for Use with CYP3A Inhibitors
`2.3
`
` Recommended dosage modifications are described below [see Drug Interactions (7.1)]:
`
`
`
`
`Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors
`
`
`
` Patient Population Coadministered Drug
`
` B-Cell Malignancies
`
`
` • Moderate CYP3A inhibitor
`
`
`
`• Voriconazole 200 mg twice daily
`
`
`• Posaconazole suspension 100 mg
`
`once daily, 100 mg twice daily, or
`
`
` 200 mg twice daily
`• Posaconazole suspension 200 mg
`
`three times daily or 400 mg twice
`
`
`daily
`
`• Posaconazole intravenously 300 mg
`
`
`once daily
`
`• Posaconazole delayed-release tablets
`
`300 mg once daily
`
`
`
`
`• Other strong CYP3A inhibitors
`
`Patients 12 years
`
`and older with
`
`cGVHD
`
`
`
`• Moderate CYP3A inhibitor
`
`
`Reference ID: 5035070
`
`
`
` Recommended IMBRUVICA Dosage
`
` 280 mg once daily
` Modify dose as recommended [see
`
`
` Dosage and Administration (2.2)].
`140 mg once daily
`
`Modify dose as recommended [see
`
`
`Dosage and Administration (2.2)].
`
`70 mg once daily
`
`
`
`Interrupt dose as recommended [see
`
`Dosage and Administration (2.2)].
`
`
`Avoid concomitant use.
`If these inhibitors will be used short-
`
`
`term (such as anti-infectives for seven
`
`
`days or less), interrupt IMBRUVICA.
`
`420 mg once daily
`
`Modify dose as recommended [see
`
`
`Dosage and Administration (2.2)].
`
`
`7
`
`

`

`
`
`
`
`
` Patient Population Coadministered Drug
` • Voriconazole 200 mg twice daily
`
`
` • Posaconazole suspension 100 mg
`
` once daily, 100 mg twice daily, or
`
`
` 200 mg twice daily
`
`
`
` Recommended IMBRUVICA Dosage
`
` 280 mg once daily
` Modify dose as recommended [see
`
`
` Dosage and Administration (2.2)].
`
`
`• Posaconazole suspension 200 mg
`
`
`
`three times daily or 400 mg twice
`
`daily
`
`
`• Posaconazole intravenously 300 mg
`
`once daily
`
`• Posaconazole delayed-release tablets
`
` 300 mg once daily
` • Other strong CYP3A inhibitors
`
`
`
`
`
`
`
`
` Patients 1 year to
`
`
` less than 12 years of
`
` age with cGVHD
`
`
`
` • Moderate CYP3A inhibitors
`
`
`
`
`
`• Voriconazole for suspension 9 mg/kg
` (maximum dose: 350 mg) twice daily
`
`
`
` • Posaconazole at any dosage
`
`
`
`
` 140 mg once daily
`
` Interrupt dose as recommended [see
`
`
` Dosage and Administration (2.2)].
`
`
`Avoid concomitant use.
`If these inhibitors will be used short-
`
`
`term (such as anti-infectives for seven
` days or less), interrupt IMBRUVICA.
`
`
` 240 mg/m2 once daily
`Modify dose as recommended [see
`
`
`Dosage and Administration (2.2)].
`
`
`
` 160 mg/m2 once daily
`
`
`
` 80 mg/m2 once daily
`
`
`
`• Other strong CYP3A inhibitors
`
`
`
`
`Avoid concomitant use.
`
`If these inhibitors will be used short-
`term (such as anti-infectives for seven
`
`
` days or less), interrupt IMBRUVICA.
`
`
` After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
`
`
`
`and Administration (2.1), Drug Interactions (7.1)].
`2.4
` Dosage Modifications for Use in Hepatic Impairment
`
` Adult Patients with B-cell Malignancies
`The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-
`
` Pugh class A).
` The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-
`Pugh class B).
` Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
`
`
` [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
` Patients with cGVHD
`
`
`
`
`
`
`
`Reference ID: 5035070
`
`
`8
`
`

`

`
`
`
` The recommended dosage is 140 mg daily for patients 12 years of age and older with total
`
`
`
`bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to
`Gilbert’s syndrome).
`
` The recommended dosage is 80 mg/m2 daily for patients 1 to less than 12 years of age with total
`
`bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
`
`Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of
`
`
`non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations (8.6), Clinical
`
`Pharmacology (12.3)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Capsules:
`
`Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
`
`
`Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
`
`Tablets:
`
`Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and
`“140” on the other side.
`
`Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the
`
`other side.
`
`Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and
`“420” on the other side.
`
`Each 560 mg tablet is a yellow to orange oblong tablet debossed with “ibr” on one side and
`
`“560” on the other side.
`
`Oral Suspension:
`
`70 mg/mL, white to off-white suspension.
`4
`CONTRAINDICATIONS
`
`
`None
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`5.1 Hemorrhage
`
`Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage
`
`(≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage
`
`
`
`[including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural
`
`hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who
`
`received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and
`petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients
`
`
`who received IMBRUVICA, respectively [see Adverse Reactions (6.1)].
`
`
`
`9
`
`Reference ID: 5035070
`
`

`

`
`
`
` The mechanism for the bleeding events is not well understood.
`
`
` Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the
`risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received
`IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The
`
`
`addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to
`4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased
`this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy
`
`
`when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.
`
`Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-
`
`
`surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
`
`
`
`5.2
`Infections
`
`
`Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with
`IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients who
`received IMBRUVICA in clinical trials [see Adverse Reactions (6.1, 6.2)]. Cases of progressive
`
`
`
`multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have
`
`occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of
`
`
`care in patients who are at increased risk for opportunistic infections. Monitor and evaluate
`
`patients for fever and infections and treat appropriately.
`
`Cardiac Arrhythmias, Cardiac Failure, and Sudden Death
`5.3
`
`
`Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA.
`
`
`Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received
`
`IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved
`monotherapy or combination regimens. These adverse reactions occurred in patients with and
`without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities
`
`
`may be at greater risk of these events.
`
`
`
`Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial
`
`
`fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was
`
`
`reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in
`patients who received IMBRUVICA in unapproved monotherapy or combination regimens.
`These events have occurred particularly in patients with cardiac risk factors including
`
`
`hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients
`
`
`with acute infections [see Adverse Reactions (6.1)].
`
`
`Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias
`
`
`and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for
`
`
`patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest
`
`pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and
`
`cardiac failure appropriately, follow dose modification guidelines [see Dosage and
`
`Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
`
`5.4 Hypertension
`
`
`
`
`10
`
`Reference ID: 5035070
`
`

`

`
`
`
` Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials.
`
`
`
` Grade 3 or greater hypertension occurred in 8% of patients [see Adverse Reactions (6.1)]. Based
`on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to
`24 months).
`
`
`Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive
`
`
`medication throughout treatment with IMBRUVICA as appropriate, and follow dosage
`
`modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration
`(2.2)].
`
`Cytopenias
`5.5
`
`
`In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3
`
`
`or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3
`or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].
`
`
`Monitor complete blood counts monthly.
`
`5.6
`Second Primary Malignancies
`
`
`Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the
`
`
`1,476 patients who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1)]. The
`
`
`
`
`most frequent second primary malignancy was non-melanoma skin cancer (6%).
`
`
`
`5.7
`Tumor Lysis Syndrome
`
`
`Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse
`
`Reactions (6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate
`
`
`precautions. Monitor patients closely and treat as appropriate.
`
`5.8
`Embryo-Fetal Toxicity
`
`
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`
`
`pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
`
`organogenesis caused embryo-fetal toxicity including malformations at exposures that were
`
`2-20 times higher than those reported in patients with hematologic malignancies. Advise
`
`
`pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use
`
`
`effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
`[see Use in Specific Populations (8.1)].
`
`
`ADVERSE REACTIONS
`6
`
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`
`• Hemorrhage [see Warnings and Precautions (5.1)]
`
`
`
`Infections [see Warnings and Precautions (5.2)]
`
`
`
`•
`• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions
`
`
`
`
`(5.3)]
`• Hypertension [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
`11
`
`Reference ID: 5035070
`
`

`

`
`
`
`
`
` • Cytopenias [see Warnings and Precautions (5.5)]
`
`
`
` • Second Primary Malignancies [see Warnings and Precautions (5.6)]
`
`
` • Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
`
`
`
`6.1
` Clinical Trials Experience
`
` Because clinical trials are conducted under widely variable conditions, adverse event rates
`
` observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`
`
` another drug and may not reflect the rates observed in practice. The pooled safety population
` described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6
`
`trials administered as a single agent at 420 mg orally once daily (475 patients) or at 560 mg
`orally once daily (174 patients), and in 4 trials administered in combination with other drugs at
`
`420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled
`
`safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were
`
`
`exposed for greater than one year; the most common adverse reactions (≥30%) were
`
`
`thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and
`bruising.
`Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received
`IMBRUVICA in unapproved monotherapy or combination regimens.
`
`Mantle Cell Lymphoma
`
`The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that
`
`
`included 111 patients with previously treated MCL treated with 560 mg daily with a median
`treatment duration of 8.3 months.
`The most common adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia,
`
`
`
`
`
`
`
`
`
`anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea,
`
`
`
`bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Table
`
`5 and Table 6).
`
`
`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 ULN occurred in 9% of patients.
`
`
`Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily
`
`
`occurring at a rate of ≥ 10% are presented in Table 5.
`
`
`
`Reference ID: 5035070
`
`
`12
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` General disorders and
`
` administration site
`
` conditions
`
`
`
`Musculoskeletal and
` connective tissue disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
`
` All Grades
`
` Grade 3 or
`
` Higher (%)
`
`
` (%)
`
`
` 51
` 5
`31
`0
`25
`0
`24
`5
`23
`0
`17
`1
`
` 11
`
` 0
`
` 41
`
` 5
`
` 35
`
` 3
`
` 18
`
` 1
`
` 14
`
` 3
`
` 37
`
` 1
`14
`0
`
` 11
`
` 0
`
` 34
`
` 0
`14
`3
`8†
`14
`
`14
`5
`
` 1
`
` 13
`
` 0
`
` 30
`3
`25
`
` 0
`
` 11
`
` 5†
`
` 27
`
` 0
`
` 19
`
` 0
`
` 11
`
` 2
`
` 21
`
` 4
`
` 12
`
` 0
`
` 14
`
` 0
`
` 13
`
` Body System
` Adverse Reaction
`
` Gastrointestinal disorders Diarrhea
`
`
` Nausea
` Constipation
`
` Abdominal pain
`
` Vomiting
`
` Stomatitis
`
` Dyspepsia
`
` Fatigue
` Peripheral edema
`
` Pyrexia
` Asthenia
`
` Musculoskeletal pain
`
` Muscle spasms
` Arthralgia
`
` Infections and infestations Upper respiratory tract infection
`
`
` Urinary tract infection
`
`
`
` Pneumonia
` Skin infections
`
` Sinusitis
` Bruising
`
`
` Rash
` Petechiae
`
`
` Dyspnea
`
` Cough
` Epistaxis
`
` Metabolism and nutrition
` Decreased appetite
`
` disorders
`
` Dehydrati