`
` 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 (1.5, 1.6)
`
`
`
`
`
`
`Dosage and Administration (2.2, 2.3, 2.4)
`
`
`
`Warnings and Precautions (5)
`
`
`
`
`
`
`
`
`
`
`08/2017
`
`08/2017
`
`01/2017
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IMBRUVICA is a kinase inhibitor indicated for the treatment of adult patients
`
`with:
` Mantle cell lymphoma (MCL) who have received at least one prior therapy
`
`
`
`
`
`
`
`
`
`
`
`
`
`(1.1).
`
`
`
`
`
`
`
`
`
`Accelerated approval was granted for this indication based on overall
`
`
`
`
`
`
`
`
`response rate. Continued approval for this indication may be contingent
`
`
`
`
`
`
`
`
`
`upon verification and description of clinical benefit in a confirmatory
`
`trial.
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`
`
`
`
`
`
`
`
`(SLL) (1.2).
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma
`
`
`
`
`
`
`
`
`
`
`
`(SLL) with 17p deletion (1.3).
` Waldenström’s macroglobulinemia (WM) (1.4).
`
`
`
`
`
` Marginal zone lymphoma (MZL) who require systemic therapy and have
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`received at least one prior anti-CD20-based therapy (1.5).
`
`
`
`
`
`
`
`
`
`Accelerated approval was granted for this indication based on overall
`
`
`
`
`
`
`
`
`response rate. Continued approval for this indication may be contingent
`
`
`
`
`
`
`
`
`
`upon verification and description of clinical benefit in a confirmatory
`
`trial.
` Chronic graft versus host disease (cGVHD) after failure of one or more
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lines of systemic therapy (1.6).
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
` MCL and MZL: 560 mg taken orally once daily (four 140 mg capsules
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`once daily) (2.2).
` CLL/SLL, WM, and cGVHD: 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)
`
`
`
`
`
`1.3
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`
`1.1 Mantle Cell Lymphoma
`
`
`
`1.2
`Chronic Lymphocytic Leukemia/Small Lymphocytic
`
`
`
`
`
`Lymphoma
`Chronic Lymphocytic Leukemia/Small Lymphocytic
`
`
`
`
`
`Lymphoma with 17p deletion
`
`
`
`
`1.4 Waldenström’s Macroglobulinemia
`
`1.5 Marginal Zone Lymphoma
`
`
`
`
`1.6
`Chronic Graft versus Host Disease
`
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Dosing Guidelines
`
`
`
`2.2 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
`
`
`
`Clinical Trials Experience
`6.1
`
`
`
`6.2
`Postmarketing Experience
`
`------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`None (4)
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
` Hemorrhage: Monitor for bleeding and manage (5.1).
`
`
`
`
`
`
`
`
`
` Infections: Monitor patients for fever and infections, evaluate promptly,
`
`
`
`
`
`
`
`
`and treat (5.2).
`
`
`
` Cytopenias: Check complete blood counts monthly (5.3).
`
`
`
`
`
`
`
` Atrial Fibrillation: Monitor for atrial fibrillation and manage (5.4).
`
`
`
`
`
`
`
`
`
` Hypertension: Monitor blood pressure and treat (5.5).
`
`
`
`
`
`
`
`
` Second Primary Malignancies: Other malignancies have occurred in
`
`
`
`
`
`
`
`
`patients, including skin cancers, and other carcinomas (5.6).
`
`
`
`
`
` Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
`
`
`
`
`
`
`
`
`Monitor and treat for TLS (5.7).
`
`
`
`
`
`
` Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`
`
`
`
`
`
`
`
`
`
`
`potential risk to a fetus and to avoid pregnancy while taking the drug and
`
`
`
`
`
`
`
`
`
`
`
`
`for 1 month after cessation of therapy. Advise men to avoid fathering a
`
`
`
`
`
`
`
`
`
`
`
`
`child during the same time period (5.8, 8.3).
`
`
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`The most common adverse reactions (≥20%) in patients with B-cell
`
`
`
`
`
`
`
`
`
`malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia,
`
`
`
`
`
`
`
`thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea,
`
`
`
`
`
`
`bruising, fatigue, hemorrhage, and pyrexia (6).
`
`
`
`
`
`
`
`The most common adverse reactions ( ≥20%) in patients with cGVHD were
`
`
`
`
`
`
`
`
`
`fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis,
`
`
`
`
`
`
`nausea, hemorrhage, anemia, and pneumonia (6).
`
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`
`
`
`
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
`
`
`
`
`
`
`
`
`
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS-----------------------------­
` CYP3A Inhibitors: Dose adjustments may be recommended (2.4, 7.1).
`
`
`
`
`
`
`
`
`
`
` CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
`
`
`
`
`
`
`
`
`(7.2).
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`
`
`
`
`
`Hepatic Impairment (based on Child-Pugh criteria): Avoid use of
`
`
`
`
`
`
`
`
`
`IMBRUVICA in patients with moderate or severe baseline hepatic
`
`
`
`
`
`
`
`
`impairment. In patients with mild impairment, reduce IMBRUVICA dose
`
`
`
`
`
`
`
`
`(2.5, 8.6).
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`
`
`
`
`
`
`approved patient labeling.
`
`
`
`
`
`Revised: 08/2017
`
`
`
`
`7
`
`
`DRUG INTERACTIONS
`
`
`
`7.1
`Effect of CYP3A Inhibitors on Ibrutinib
`
`
`
`
`
`
`
`7.2
`Effect of CYP3A Inducers on Ibrutinib
`
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`Pregnancy
`8.1
`
`
`8.2
`Lactation
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Impairment
`
`
`
`8.7
`Plasmapheresis
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`
`
`14.1 Mantle Cell Lymphoma
`
`
`
`
`
`
`14.2 Chronic Lymphocytic Leukemia / Small Lymphocytic
`
`Lymphoma
`
`
`14.3 Waldenström’s Macroglobulinemia
`
`
`
`
`14.4 Marginal Zone Lymphoma
`
`
`
`
`
`14.5 Chronic Graft versus Host Disease
`
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information are
`
`
`not listed.
`
`Reference ID: 4133530
`
`
`
` 1
`
`

`

`
`
`
`
` 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.
`
`Accelerated approval was granted for this indication based on overall response rate. Continued
`
`approval for this indication may be contingent upon verification and description of clinical
`
`benefit in a confirmatory trial [see Clinical Studies (14.1)].
`
`
`
`
`
`1.2
`
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`
`
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`
`
`
`(CLL)/small lymphocytic lymphoma (SLL) [see Clinical Studies (14.2)].
`
`
`
`
`1.3
`
`
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
`
`
`IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
`
`
`
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion [see Clinical Studies (14.2)].
`
`
`
`
`
`1.4 Waldenström’s Macroglobulinemia
`
`
`
`IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
`
`
`macroglobulinemia (WM) [see Clinical Studies (14.3)].
`
`
`
`1.5 Marginal Zone Lymphoma
`
`
`
`IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma
`
`
`
`(MZL) who require systemic therapy and have received at least one prior anti-CD20-based
`
`
`
`therapy.
`
`
`Accelerated approval was granted for this indication based on overall response rate [see Clinical
`
`
`
`Studies (14.4)]. Continued approval for this indication may be contingent upon verification and
`
`
`description of clinical benefit in a confirmatory trial.
`
`
`
`1.6
`
`
`Chronic Graft versus Host Disease
`
`
`
`
`IMBRUVICA is indicated for the treatment of adult patients with chronic graft-versus-host
`
`
`
`
`disease (cGVHD) after failure of one or more lines of systemic therapy [see Clinical Studies
`
`
`
`(14.5)].
`
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`
`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.
`
`
`Reference ID: 4133530
`
`
`2
`
`

`

`
`
`
`
` 2.2
`
`
`
` Dosage
`
`
`
` Mantle Cell Lymphoma and Marginal Zone Lymphoma
`
`
`
`
`
`
`
`
`
`
`
` The recommended dose of IMBRUVICA for MCL and MZL is 560 mg (four 140 mg capsules)
`
`
`
`
`
` orally once daily until disease progression or unacceptable toxicity.
`
`
`
`
`
` Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
`
`
`
`
`
` Macroglobulinemia
`
`
`
`
`
`
`
` The recommended dose of IMBRUVICA for CLL/SLL and WM is 420 mg (three 140 mg
`
`
`
`
`
` capsules) orally once daily until disease progression or unacceptable toxicity.
`
`
`
`
`
`
`
` The recommended dose of IMBRUVICA for CLL/SLL when used in combination with
`
`
`
` bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg
`
`
`
`
`
`
`
` (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.
`
`
`
`
`
` Chronic Graft versus Host Disease
`
`
`
`
`
`
`
`
`
`
`
` The recommended dose of IMBRUVICA for cGVHD is 420 mg (three 140 mg capsules) orally
`
`
`
`
`
` once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable
`
`
`
`
`
` toxicity. When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA
`
`
`
`
`
`
`
` should be discontinued considering the medical assessment of the individual patient.
`
`
`
` 2.3
`
`
`
` Dose Modifications for Adverse Reactions
`
`
`
`
`
` Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological toxicities, Grade 3
`
` or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the
`
`
`
`
`
` symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy
`
`
`
`
`
`
`
`
`
` may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule
`
`
`
`
`
` (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these
`
`
`
`
`
`
`
`
`
` toxicities persist or recur following two dose reductions, discontinue IMBRUVICA.
`
`
`
`
`
`
`
` Toxicity Occurrence
`
`
`
` First
`
`
`
` Second
`
`
`
` Third
`
`
`
` Fourth
`
`
`
` Recommended dose modifications are described below:
`
`
`
` Dose Modification for MCL and
` MZL After Recovery
`
`
` Starting Dose = 560 mg
`
`
`
`
`
`
`Dose Modification for CLL/SLL,
`
`
` WM, and cGVHD After Recovery
` Starting Dose = 420 mg
`
`
`
`
`
`
`
`
`
`
` Restart at 560 mg daily
`
`
`
`
`
`
`
` Restart at 420 mg daily
`
`
`
`
`
` Restart at 420 mg daily
`
`
`
`
`
`
`
` Restart at 280 mg daily
`
`
`
`
`
`
`
`
`
` Restart at 280 mg daily
`
`
`
`
`
`
`
` Restart at 140 mg daily
`
`
`
`
`
` Discontinue IMBRUVICA
`
`
`
` Discontinue IMBRUVICA
`
`Reference ID: 4133530
`
`
`3
`
`

`

`
`
`
`
` 2.4
`
`
`
` Dose Modifications for Use with CYP3A Inhibitors
`
`
`
`
`
`
`
` Recommended dose modifications are described below [see Drug Interactions (7.1)]:
`
`
`
` Patient Population Coadministered Drug
`
`
`
`
`
`
`
` Recommended IMBRUVICA Dose
`
`
`140 mg once daily
`
` Interrupt dose as recommended [see
`
`
`
`
` Dosage and Administration (2.3)].
`
`
`
`
`
`
`
` Avoid concomitant use.
`
`
`
` If these inhibitors will be used short-
` term (such as anti-infectives for seven
`
`
` days or less), interrupt IMBRUVICA.
`
`
`
`B-Cell Malignancies  Moderate CYP3A inhibitor
`
`
`
`
` Posaconazole at doses less than or
`
`
`
`
`
` equal to 200 mg BID
` Voriconazole at any dose
`
`
`
`
` Posaconazole at doses greater than
`
`
` 200 mg BID
` Other strong CYP3A inhibitors
`
`
`
`
`
`
`
`
` Chronic Graft versus
`
` Host Disease
`
` Moderate CYP3A inhibitor
`
`
`
`
`
` 420 mg once daily
`
`
`
`
`
` Modify dose as recommended [see
`
` Dosage and Administration (2.3)].
`
` Posaconazole immediate-release
`
`
` tablet 200 mg BID or delayed-release
`
` tablet 300 mg QD
`
` Voriconazole at any dose
`
`
`
`
` Posaconazole at other higher doses
`
`
` Other strong CYP3A inhibitors
`
`
`
`
`
`
` 280 mg once daily
`
`
`
`
` Modify dose as recommended [see
` Dosage and Administration (2.3)].
`
`
`
`
`
`
`
` Avoid concomitant use.
`
`
`
` If these inhibitors will be used short-
` term (such as anti-infectives for seven
`
` days or less), interrupt IMBRUVICA.
`
`
`
`
`
` 2.5
`
`
`
` Dose Modifications for Use in Hepatic Impairment
`
`
`
`
`
`
`
` The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh
`
`
`
`
`
`
`
` class A). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic impairment
`
`
`
`
`
` (Child-Pugh classes B and C) [see Use in Specific Populations (8.6) and Clinical Pharmacology
`
`
`
` (12.3)].
`
`
`
` 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.
`
`
`
`
`3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` 140 mg capsules
`
`
`4
`
`
`
` CONTRAINDICATIONS
`
`
`
` None
`
`Reference ID: 4133530
`
`
`4
`
`

`

`
`
`
`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)].
`
`
`
`
`
` 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 14% to 29% of patients [see
`
`
`
`
`
` Adverse Reactions (6.1, 6.2)]. Cases of progressive multifocal leukoencephalopathy (PML) and
`
`
`
` Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA.
`
`
`
`
`
`
` Consider prophylaxis according to standard of care in patients who are at increased risk for
`
`
`
`
`
` opportunistic infections. Monitor and evaluate patients for fever and infections and treat
`
`
`
` appropriately.
`
`
`
` 5.3
`
`
`
` Cytopenias
`
` Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%),
`
`
`
`
`
`
`
`
`
`
`
` thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory
`
`
`
`
`
` measurements occurred in patients with B-cell malignancies treated with single agent
`
`
`
`
`
` IMBRUVICA.
`
`
`
` Monitor complete blood counts monthly.
`
`
`
`
`
` 5.4
`
`
`
` Atrial Fibrillation
`
`
`
`
`
`
`
`
`
` Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with
`
`
`
`IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections,
`
`and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial
`
`
`fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or
`
`
`new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed
`
`
`
`
`
`
`appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and
`
`
` follow dose modification guidelines [see Dosage and Administration (2.3)].
`
`
`
`
`
`
`
`Reference ID: 4133530
`
`
`5
`
`

`

`
`
`
`
` 5.5 Hypertension
`
`
`
`
`
`
`
`
`
` Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a
`
`
`
`
`
`
`
`
`
`
`
`
`
` median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset
`
`
`
`
`
`
`
` hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.
`
`
`
`Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as
`
`appropriate.
`
`
`5.6
`
`
`Second Primary Malignancies
`
`
`Other malignancies (range, 3 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, 2 to 13%).
`
`
`
`5.7
`
`
`Tumor Lysis Syndrome
`
`
`Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the
`
`
`
`baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely
`
`
`
`and treat as appropriate.
`
`
`5.8
`
`
`Embryo-Fetal Toxicity
`
`
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`
`pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
`
`
`
`organogenesis caused embryofetal toxicity including malformations at exposures that were
`
`
`
`
`2-20 times higher than those reported in patients with hematologic malignancies. Advise women
`
`
`
`
`to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of
`
`
`
`therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking
`
`
`
`this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific
`
`Populations (8.1)].
`
`
`
`
`6
`
`ADVERSE REACTIONS
`
`
`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: 4133530
`
`
`6
`
`

`

`
`
`
`
` 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.
`
`
`
`
`Mantle Cell Lymphoma
`
`
`
`
`
`The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that
`
`
`included 111 patients with previously treated MCL treated with 560 mg daily with a median
`
`
`treatment duration of 8.3 months.
`
`
`The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
`
`neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract
`
`infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased
`
`
`
`
`appetite (see Tables 1 and 2).
`
`
`
`The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
`
`
`abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
`
`
`Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in
`
`
`creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.
`
`
`
`Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily
`
`
`
`
`
`occurring at a rate of ≥ 10% are presented in Table 1.
`
`
`
`
`Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
`
`
`
`
`
`
`
` Adverse Reaction
` Body System
`
`
` Gastrointestinal disorders Diarrhea
`
`
` Nausea
` Constipation
`
`
` Abdominal pain
`
` Vomiting
`
` Stomatitis
`
` Dyspepsia
` Infections and infestations Upper respiratory tract
`
` infection
`
` Urinary tract infection
`
` Pneumonia
`
` Skin infections
`
` Sinusitis
`
`
`
`
`
` Fatigue
`
`
`
` Peripheral edema
`
`
`
`
`
` Pyrexia
`
`
`
` Asthenia
`
`General disorders and
`administration site
`
` conditions
`
`Reference ID: 4133530
`
`
`
`
`
`
` All Grades (%)
`
` 51
`
` 31
`
` 25
`
` 24
`
` 23
`
` 17
`
` 11
`
`
`
` 34
`
` 14
`
` 14
`
` 14
`
` 13
`
`
`
` 41
`
`
`
` 35
`
`
`
` 18
`
`
`
` 14
`
` Grade 3 or 4 (%)
`
`
`
` 5
`
` 0
`
` 0
`
` 5
`
` 0
`
` 1
`
` 0
`
`
`
` 0
`
` 3
`
` 7
`
` 5
`
` 1
`
`
`
` 5
`
`
`
` 3
`
`
`
` 1
`
`
`
` 3
`
`
`7
`
`

`

`
`
`
`
` Body System
`
`Skin and subcutaneous
`
` tissue disorders
`
`
`
` Adverse Reaction
`
` Bruising
`
` Rash
` Petechiae
`
`
`
`
`
`
`
`
` All Grades (%)
`
` 30
`
` 25
`
` 11
`
` Musculoskeletal and
`
` connective tissue disorders
`
`
`
`
` Musculoskeletal pain
`
` Muscle spasms
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
`
`
` Arthralgia
`
`
`
` Dyspnea
`
`
`
` Cough
`
`
`
` Epistaxis
`
`
`
` Metabolism and nutrition
`
` disorders
`
`
` Decreased appetite
`
` Dehydration
`
`
`
` Nervous system disorders
`
`
` Dizziness
`
` Headache
`
`
` 37
`
` 14
`
`
`
` 11
`
`
`
` 27
`
`
`
` 19
`
`
`
` 11
`
`
` 21
`
` 12
`
`
` 14
`
` 13
`
` Grade 3 or 4 (%)
`
`
`
` 0
`
` 3
`
` 0
`
`
` 1
`
` 0
`
`
`
` 0
`
`
`
` 4
`
`
`
` 0
`
`
`
` 0
`
`
` 2
`
` 4
`
`
` 0
`
` 0
`
`
`
` Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities
`
`
`
` in Patients with MCL (N=111)
`
`
`
`
`
`
`
`
` Platelets Decreased
`
`
`
`
`Neutrophils Decreased
`
`
` Hemoglobin Decreased
`
`
`
`
`
`
` Percent of Patients (N=111)
`
`
`
`
` All Grades (%)
`
`
`
`
` Grade 3 or 4 (%)
`
`
`
`
`57
`
`
`47
`
`
`41
`
`
`17
`
`
`29
`
`
`9
`
` * Based on laboratory measurements and adverse reactions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most
`
`
`
`frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).
`
`
`
` Adverse reactions leading to dose reduction occurred in 14% of patients.
`
`
`
`
`
` Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed
`
`intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases
`
`
`
` were in the setting of disease progression.
`
`
`
` Forty percent of patients had elevated uric acid levels on study including 13% with values above
`
`
`
` 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.
`
`
`
` Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`
`
`
`
`
`
`The data described below reflect exposure in one single-arm, open-label clinical trial
`
`
`
`
`
`(Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and
`
`
`
`HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to
`
`
`
`IMBRUVICA). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE
`
`
`included 391 randomized patients with previously treated CLL or SLL who received single agent
`
`
`
`
`
`IMBRUVICA or ofatumumab, RESONATE-2 included 269 randomized patients 65 years or
`
`older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or
`
`
`
`chlorambucil, and HELIOS included 578 randomized patients with previously treated CLL or
`
`
`8
`
`Reference ID: 4133530
`
`

`

`
`
`SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in
`
`combination with bendamustine and rituximab.
`
`
`The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2,
`
`
`
`and HELIOS in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia,
`
`
`
`
`
`thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue,
`
`
`pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1102,
`
`
`
`
`RESONATE, RESONATE-2, and HELIOS discontinued treatment due to adverse reactions.
`
`
`
`
`These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each).
`
`
`
`
`
`Adverse reactions leading to dose reduction occurred in approximately 6% of patients.
`
`
`
`
`Study 1102
`
`
`Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single
`
`
`
`
`agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a
`
`
`
`
`
`rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3
`
`
`
`and 4.
`
`
`
`Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`CLL/SLL (N=51) in Study 1102
`
`
`
`
`
`
`
`
`
`
` Body System
`
`
`
` Adverse Reaction
`
`
`
` All Grades (%)
`
`
` Grade 3 or 4
`
` (%)
`
`
`
` Gastrointestinal disorders
`
`
`
` Infections and infestations
`
` Diarrhea
`
`
` Constipation
`
` Nausea
`
` Stomatitis
`
` Vomiting
`
` Abdominal pain
`
` Dyspepsia
`
`
`
`
`
` Upper respiratory tract infection
`
` Sinusitis
`
` Skin infection
`
` Pneumonia
` Urinary tract infection
`
`
`
`
`General disorders and
`
` administration site
`
` conditions
`
` Fatigue
`
` Pyrexia
`
`
`
` Peripheral edema
` Asthenia
`
`
` Chills
`
`
`
` Bruising
`
` Rash
` Petechiae
`
`
`
`Skin and subcutaneous tissue
`
` disorders
`
`Reference ID: 4133530
`
`
` 59
`
` 22
`
` 20
`
` 20
`
` 18
`
` 14
`
` 12
`
`
` 47
`
` 22
`
` 16
`
` 12
`
` 12
`
`
` 33
`
` 24
`
` 22
`
` 14
`
` 12
`
`
` 51
`
` 25
`
` 16
`
`
` 4
`
` 2
`
` 2
`
` 0
`
` 2
`
` 0
`
` 0
`
`
` 2
`
` 6
`
` 6
`
` 10
`
` 2
`
`
` 6
`
` 2
`
` 0
`
` 6
`
` 0
`
`
` 2
`
` 0
`
` 0
`
`
`9
`
`

`

`
`
`
`
` Body System
`
`
`
` Adverse Reaction
`
`
`
` All Grades (%)
`
`
` Grade 3 or 4
`
` (%)
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
` Musculoskeletal and
`
` connective tissue disorders
`
`
`
`
` Nervous system disorders
`
`
`
`
`
` Metabolism and nutrition
`
` disorders
`
` Neoplasms benign,
`
` malignant, unspecified
`
`
` Cough
`
` Oropharyngeal pain
`
` Dyspnea
`
`
`
`
`
` Musculoskeletal pain
`
` Arthralgia
` Muscle spasms
`
`
`
` Dizziness
`
` Headache
`
`
`
` Decreased appetite
`
`
`
` Second malignancies*
`
`
`
` Hypertension
` Vascular disorders
`
`
`
` *One patient death due to histiocytic sarcoma.
`
`
`
`
`
`
`
`
` 22
`
` 14
`
` 12
`
`
` 25
`
` 24
`
` 18
`
`
` 20
`
` 18
`
`
`
` 16
`
`
`
` 12*
`
`
`
` 16
`
`
` 0
`
` 0
`
` 0
`
`
` 6
`
` 0
`
` 2
`
`
` 0
`
` 2
`
`
`
` 2
`
`
`
` 0
`
`
`
` 8
`
`
`
` Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities
`
`
`
`
`
` in Patients with CLL/SLL (N=51) in Study 1102
`
`
`
`
`
`
`Platelets Decreased
`
`
`Neutrophils Decreased
`
`
`Hemoglobin Decreased
`
`
` Percent of Patients (N=51)
`
`
`
`
`All Grades (%)
`
`
` Grade 3 or 4 (%)
`
`
`
`
`69
`
`
`53
`
`
`43
`
`
`12
`
`
`26
`
`
`0
`
` * Based on laboratory measurements per IWCLL criteria and adverse reactions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` RESONATE
`
`
`
` Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect
`
`
`
`
`
`exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
`
`
`
` with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.
`
`
`
`Reference ID: 4133530
`
`
`10
`
`

`

`
`
`Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`
`
`
`
`
`
`
`IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE
`
`
`
`
`
`
`
` IMBRUVICA
`
`(N=195)
`
`
` Ofatumumab
`
`(N=191)
`
`
`Body System
`
`Adverse Reaction
`
`
` All Grades
`
`(%)
`
`
` Grade 3 or 4
`
`(%)
`
`
` All Grades
`
`(%)
`
`
` Grade 3 or 4
`
`(%)
`
`
`Gastrointestinal disorders
`
`
`Diarrhea
`
`
`Nausea
`
`
`Stomatitis*
`
`
`Constipation
`
`
`Vomiting
`
`General disorders and
`
`administration site conditions
`
`
`Pyrexia
`
`
`Infections and infestations
`
`
` Upper respiratory tract
`
`infection
`
`
`
`
`Pneumonia*
`
`
`Sinusitis*
`
`
`
`
`
`
`48
`
`
`26
`
`
`17
`
`
`15
`
`
`14
`
`
`
`
`24
`
`
`
`
`16
`
`
`15
`
`
`11
`
`
`
`
`4
`
`
`2
`
`
`1
`
`
`0
`
`
`0
`
`
`
`
`2
`
`
`
`
`1
`
`
`10
`
`
`1
`
`
`
`
`18
`
`
`18
`
`
`6
`
`
`9
`
`
`6
`
`
`
`
`15
`
`
`
`
`11
`
`
`13
`
`
`6
`
`
`5
`
`
`
`
`2
`
`
`0
`
`
`1
`
`
`0
`
`
`1
`
`
`
`
`1
`
`
`
`
`2
`
`
`9
`
`
`0
`
`
`1
`
`
` 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
`
`
`Contusion
`
`
`Eye disorders
`
`
`10
`
`
`
`
`24
`
`
`14
`
`
`12
`
`
`
`
`28
`
`
`17
`
`
`
`
`14
`
`
`11
`
`
`
`
`11
`
`
`
`
`4
`
`
`
`
`3
`
`
`0
`
`
`0
`
`
`
`
`2
`
`
`1
`
`
`
`
`1
`
`
`0
`
`
`
`
`0
`
`
`
`
`
`
`13
`
`
`1
`
`
`1
`
`
`
`
`18
`
`
`7
`
`
`
`
`6
`
`
`5
`
`
`
`
`3
`
`
`
`
`
`
`0
`10
`Vision blurred
`Subjects with multiple events for a given ADR term are counted once only for each ADR term.
`
`
`
`
`
`
`
`
`
`
`
`The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` * Includes multiple ADR terms
`
`
`
`3
`
`
`
`
`0
`
`
`0
`
`
`0
`
`
`
`
`1
`
`
`0
`
`
`
`
`0
`
`
`0
`
`
`
`
`0
`
`
`
`
`0
`
`
`11
`
`Reference ID: 4133530
`
`

`

`Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
`
`
`
`CLL/SLL in RESONATE
`
`
`
`
`
` IMBRUVICA
`
` (N=195)
`
`
` Ofatumumab
`
` (N=191)
`
`
`
` All Grades
`
` (%)
`
`
` Grade 3 or 4
`
` (%)
`
`
` All Grades
`
` (%)
`
`
` Grade 3 or 4
`
` (%)
`
`
`
` 51
`
`
`
` 52
`
`
`
` 36
`
`
`
` 23
`
`
`
` 5
`
`
`
` 0
`
`
`
` 57
`
`
`
` 45
`
`
`
` 21
`
`
`
` 26
`
`
`
` 10
`
`
`
` 0
`
`
`
`
`
`
`
` Neutrophils Decreased
`
`
`
` Platelets Decreased
`
`
`
` Hemoglobin Decreased
`
`
`
`
`
` RESONATE-2
`
`
`
` Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median
`
`
`
` duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in
`
`
`
`
`
` RESONATE-2.
`
`
`
`
`
`
`
`
`
` Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2
`
`
`
`
`
`
`
`
` IMBRUVICA
`
`(N=135)
`
`
` Chlorambucil
`
`(N=132)
`
`
`Body System
`
`Adverse Reaction
`
`
` All Grades
`
`(%)
`
`
` Grade 3 or 4
`
`(%)
`
`
` All Grades
`
`(%)
`
`
` Grade 3 or 4
`
`(%)
`
`
`Gastrointestinal disorders
`
`
`
`
`Diarrhea
`
`
`
`
`
`
`42
`
`
`
`
`4
`
`
`1
`
`
`
`
`17
`
`
`4
`
`
`
`
`0
`
`
`1
`
`
`Stomatitis*
`
`
`14
`
` Musculoskeletal and
`
`connective tissue disorders
`
`
`
`
`
`
`
` Musculoskeletal pain*
`
`
`
`
`Arthralgia
`
`
`
`
`Muscle spasms
`
`
`Eye Disorders
`
`
`
`
`Dry eye
`
`
`
`
`
`
`Lacrimation increased
`
`Vision blurred
`
`
`
`
`Visual acuity reduced
`
`Skin and subcutaneous tissue
`
`disorders
`
`
`
`
`Rash*
`
`
`
`
`Bruising*
`
`
`Infections and infestations
`
`
`
`
`Skin infection*
`
`
`
`
`Pneumonia*
`
`
`
`36
`
`
`
`16
`
`
`
`
`11
`
`
`
`
`17
`
`
`13
`
`13
`
`
`11
`
`
`
`
`21
`
`
`19
`
`
`
`
`15
`
`
`14
`
`
`
`
`4
`
`
`1
`
`
`0
`
`
`
`
`0
`
`
`0
`
`0
`
`
`0
`
`
`
`
`4
`
`
`0
`
`
`
`
`2
`
`
`8
`
`
`
`
`20
`
`
`7
`
`
`5
`
`
`
`
`5
`
`
`6
`
`8
`
`
`2
`
`
`
`
`12
`
`
`7
`
`
`
`
`3
`
`
`7
`
`
`
`
`0
`
`
`1
`
`
`0
`
`
`
`
`0
`
`
`0
`
`0
`
`
`0
`
`
`
`
`2
`
`
`0
`
`
`
`
`1
`
`
`4
`
`
`12
`
`Reference ID: 4133530
`
`

`

`
`
`
`Body System
`
`Adverse Reaction
`
` Urinary tract infections
`
`
`
`
` Respiratory, thoracic and
`
`mediastinal disorders
`
`
`
`
`Cough
`
`General disorders and
`
`administration site conditions
`
`
`
`
`Peripheral edema
`
`
`
`
`Pyrexia
`
`
`Vascular Disorders
`
`
`
`
`Hypertension*
`
`
`Nervous System Disorders
`
`
` IMBRUVICA
`
`(N=135)
`
`
` Chlorambucil
`
`(N=132)
`
`
` All Grades
`
`(%)
`
`10
`
`
` Grade 3 or 4
`
`(%)
`
`1
`
`
` All Grades
`
`(%)
`
`8
`
`
` Grade 3 or 4
`
`(%)
`
`1
`
`
`
`
`22
`
`
`
`
`19
`
`17
`
`
`
`14
`
`
`
`
`
`
`
`
`0
`
`
`
`
`1
`
`0
`
`
`
`
`4
`
`
`
`
`
`
`15
`
`
`
`
`9
`
`14
`
`
`
`
`1
`
`
`
`
`
`
`0
`
`
`
`
`0
`
`2
`
`
`
`
`0
`
`
`
`
`2
`
`
`
`
`1
`12
`Headache
`