`
` 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
`
`Initial U.S. Approval: 2013
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`
`Dosage and Administration (2.2, 2.4)
`01/2019
`
`
`
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)
`07/2019
`
`
`
`----------------------------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 (2.2).
`
`
`
`• CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily (2.2).
`
`
`
`
`
`Dose 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 (2.1).
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`Capsules: 70 mg and 140 mg (3)
`
`
`
`
`Tablets: 140 mg, 280 mg, 420 mg, and 560 mg (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).
`
`
`• Cytopenias: Check complete blood counts monthly (5.3).
`
`
`• Cardiac arrhythmias: Monitor for symptoms of arrhythmias 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 thrombocytopenia,
`
`
`
`
`diarrhea, anemia, neutropenia, musculoskeletal pain, rash, bruising, nausea,
`
`
`
`
`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: Modify IMBRUVICA dose as described (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 severe baseline hepatic impairment. In patients
`
`with mild or moderate impairment, reduce IMBRUVICA dose (2.5, 8.6).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`
`approved patient labeling.
`
`
`
`
`Revised: 07/2019
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Mantle Cell Lymphoma
`
`
`
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`1.2
`
`
`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 Dosing Guidelines
`
`
`2.2
`Recommended 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
`Cardiac Arrhythmias
`
`
`
`
`5.5 Hypertension
`
`
`5.6
`Second Primary Malignancies
`
`
`5.7
`Tumor Lysis Syndrome
`
`
`
`5.8
`Embryo-Fetal Toxicity
`
`
`6 ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`7
`
`
`
`Postmarketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`
`Effect of CYP3A Inhibitors on Ibrutinib
`7.1
`
`
`
`
`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
`
`
`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: 4462109
`
`
`
` 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)].
`
`
`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.
`
`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.
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Dosing Guidelines
`
`
`Administer IMBRUVICA orally once daily at approximately the same time each day. The dose
`
`
`
`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.
`
`
`
`Reference ID: 4462109
`
`
`2
`
`

`

`
`
`
`
`
`
`
` Recommended Dosage
` 2.2
`
`
` Mantle Cell Lymphoma and Marginal Zone Lymphoma
`
`
`
` The recommended dose of IMBRUVICA for MCL and MZL is 560 mg 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 as a single agent, in
`
`
`combination with rituximab for WM, or in combination with bendamustine and rituximab or
`with obinutuzumab for CLL/SLL is 420 mg orally once daily until disease progression or
`
`
`unacceptable toxicity.
`
`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 dose of IMBRUVICA for cGVHD is 420 mg 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 140 mg per day. A
`
`
`
`
`second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or
`
`
`
`
`recur following two dose reductions, discontinue IMBRUVICA.
`
`
`
`Recommended dose modifications are described below:
`
`
`
`
` Toxicity Occurrence
`First
`
`
` Second
`
` Third
` Fourth
`
`
`Reference ID: 4462109
`
`
`
`
`
`
` Dose Modification for MCL and
` MZL After Recovery
`
` Starting Dose = 560 mg
`Restart at 560 mg daily
`
`
`
`
` Restart at 420 mg daily
`
`
`
` Restart at 280 mg daily
`
`
` Discontinue IMBRUVICA
`
`
`
`
`
`
`
` Dose Modification for CLL/SLL,
`
` WM, and cGVHD After Recovery
`
` Starting Dose = 420 mg
`
`Restart at 420 mg daily
`
`
`
`
` Restart at 280 mg daily
`
`
`
` Restart at 140 mg daily
`
`
` Discontinue IMBRUVICA
`
`
`
`3
`
`

`

`
` Dose Modifications for Use with CYP3A Inhibitors
` 2.4
`
`
`
`
` Recommended dose modifications are described below [see Drug Interactions (7.1)]:
`
`
`
`
`
`
` 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 IV injection 300 mg
`
`
`once daily
`
`• Posaconazole delayed-release tablets
`
`300 mg once daily
`
`
`• Other strong CYP3A inhibitors
`
`
`
`
`Chronic Graft versus
`
`Host Disease
`
`
`• 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 IV injection 300 mg
`
`
` once daily
` • Posaconazole delayed-release tablets
`
` 300 mg once daily
`
`• Other strong CYP3A inhibitors
`
`
`
`
`
`
`
`
` Recommended IMBRUVICA Dose
`
` 280 mg once daily
`Modify dose as recommended [see
`
` Dosage and Administration (2.3)].
`
`140 mg once daily
`
`
`Modify dose as recommended [see
`
`Dosage and Administration (2.3)].
`
`70 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.
`
`
`420 mg once daily
`
`Modify dose as recommended [see
`
`
`Dosage and Administration (2.3)].
`
`280 mg once daily
`Modify dose as recommended [see
`
`Dosage and Administration (2.3)].
`
` 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.
`
`
`
` After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
` and Administration (2.2) and Drug Interactions (7.1)].
`
`
`
`
`Reference ID: 4462109
`
`
`4
`
`

`

`
` Dose Modifications for Use in Hepatic Impairment
` 2.5
`
`
`The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh
`class A).
`
`The recommended dose 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) 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 doses of
`
`
`IMBRUVICA should not be taken to make up for the missed dose.
`
`
`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.
`
`
`CONTRAINDICATIONS
`4
`
`
`None
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`5.1 Hemorrhage
`
`
`Fatal bleeding events have occurred in patients treated with 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) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients
`
`
`
`
`
`exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising
`
`
`
`and petechiae, occurred in 39% of patients treated with IMBRUVICA.
`
`
`
`
`5
`
`Reference ID: 4462109
`
`

`

`
`
`
` 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. In IMBRUVICA clinical trials, 3.1% of patients taking 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 24% of 1,124 patients exposed
`
`
`
`to 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.
`
`
` 5.3
` Cytopenias
`
` Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia
`
` (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell
`
` malignancies treated with single agent IMBRUVICA.
`
`Monitor complete blood counts monthly.
`
`
`5.4
`Cardiac Arrhythmias
`
`
`Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or
`
`
`
`greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial
`
`
`
`
`fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in
`
`
`clinical trials. These events have occurred particularly in patients with cardiac risk factors,
`
`
`hypertension, acute infections, and a previous history of cardiac arrhythmias. See Additional
`
`Important Adverse Reactions (6.1).
`
`
`
`Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who
`
`develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new
`
`
`onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks
`
`
`and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage
`
`and Administration (2.3)].
`
`
`5.5 Hypertension
`
`
`6
`
`Reference ID: 4462109
`
`

`

`
`
`
`
` Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in
`clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to
`
`
`
`onset of 5.9 months (range, 0.03 to 24 months).
`
`
`
`
`Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-
`
`
`hypertensive medication throughout treatment with IMBRUVICA as appropriate.
`
`
`
`Second Primary Malignancies
`5.6
`
`
`Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients
`
`
`
`
`treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was
`
`
`
`non-melanoma skin cancer (6%).
`
`Tumor Lysis Syndrome
`5.7
`
`
`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.
`
`
`Embryo-Fetal Toxicity
`5.8
`
`
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`
`
`
`
`pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
`
`organogenesis caused embryo-fetal 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)].
`
`ADVERSE REACTIONS
`6
`
`
`The following clinically significant 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)]
`
`
`
`
`
`• Cardiac Arrhythmias [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)]
`
`
`
`
`
`Clinical Trials Experience
`6.1
`
`
`
`Reference ID: 4462109
`
`
`7
`
`

`

`
` 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.
`
`
`
`
`
`
` General disorders and
`
` administration site
`
`conditions
`
`
` Skin and subcutaneous
`
` tissue disorders
`
` Body System
` Adverse Reaction
`
`
` 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
`
`Table 1: 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
`
` 34
`
` 0
`
` 14
`
` 3
`
` 14
` 8†
`
`
`
`14
`5
`
` 13
`
` 1
`
` 41
`
` 5
`
` 35
`
` 3
`
` 18
`
` 1
`
` 14
`
` 3
`
` 30
`
` 0
`
` 25
`
` 3
`
` 11
`
` 0
`
` 37
`
` 1
`
` 14
`
` 0
`
`Musculoskeletal and
` connective tissue disorders
`
`
`
`
`
`Reference ID: 4462109
`
`
`8
`
`

`

`
`
`
`
` Body System
`
`
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
`
`
`
` All Grades
`
` (%)
`
` 11
`
` 27
`
` 19
`
` 11
`
` 21
`
` 12
`
` 14
`
` 13
`
`
` Grade 3 or
`
` Higher (%)
`
`
` 0
` 5†
`
`
` 0
`
` 0
`
` 2
`
` 4
`
` 0
`
` 0
`
`
`
`
`
` Adverse Reaction
`
` Arthralgia
`
` Dyspnea
`
` Cough
` Epistaxis
`
` Metabolism and nutrition
`
` Decreased appetite
`
` disorders
`
` Dehydration
` Nervous system disorders Dizziness
`
`
`
` Headache
` † Includes one event with a fatal outcome.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities
`
`
` in Patients with MCL (N=111)
`
`
`
`
`
`
` Percent of Patients (N=111)
`
`
`Grade 3 or 4 (%)
`All Grades (%)
`
`
`
`57
`17
`
`
`47
`29
`
`
`41
`9
`
`
`
`
`Platelets Decreased
`
`Neutrophils Decreased
`
`Hemoglobin Decreased
`
` * Based on laboratory measurements and adverse reactions
`
`
` Treatment-emergent Grade 4 thrombocytopenia (6%) and neutropenia (13%) occurred in patients.
`
`
` 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 four randomized controlled clinical trials (RESONATE, RESONATE-2, and
`
`
`
`
`
`HELIOS, and iLLUMINATE) in patients with CLL/SLL (n=1,506 total and n=781 patients
`
`
`exposed to IMBRUVICA). Patients with creatinine clearance (CrCl) ≤ 30 mL/min, AST or ALT
`
`
`
`
`
`
`
`≥ 2.5 x ULN (upper limit of normal), or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin)
`
`were excluded from these trials. Study 1102 included 51 patients with previously treated
`
`
`CLL/SLL, RESONATE included 386 randomized patients with previously treated CLL or SLL
`
`who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included
`
`267 randomized patients with treatment naïve-CLL or SLL who were 65 years or older and
`
`Reference ID: 4462109
`
`
`9
`
`

`

`
`
`
` received single agent IMBRUVICA or chlorambucil, HELIOS included 574 randomized patients
`
`
`
`
` with previously treated CLL or SLL who received IMBRUVICA in combination with
`bendamustine and rituximab or placebo in combination with bendamustine and rituximab, and
`iLLUMINATE included 228 randomized patients with treatment naïve CLL who were 65 years
`
`
`
`
`or older or with coexisting medical conditions and received IMBRUVICA in combination with
`
`
`obinutuzumab or chlorambucil in combination with obinutuzumab.
`
`The most commonly occurring adverse reactions in patients with CLL/SLL receiving
`
`
`IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, rash,
`
`
`musculoskeletal pain, bruising, nausea, fatigue, pyrexia, hemorrhage, and cough.
`
`
`Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
`
`
`
`due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and
`neutropenia. Adverse reactions leading to dose reduction occurred in approximately 7% 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
`
` Gastrointestinal disorders
`
`
`
`
`
` Infections and infestations
`
` General disorders and
`
`administration site
`
`conditions
`
`
`Reference ID: 4462109
`
`
`
`
`
`
`
`
`
` Adverse Reaction
`
` Diarrhea
`
` Constipation
`
` Nausea
`
` Stomatitis
`
` Vomiting
`
` Abdominal pain
`
` Dyspepsia
` Upper respiratory tract infection
`
` Sinusitis
`
` Skin infection
`
` Pneumonia
` Urinary tract infection
`
`Fatigue
`
`Pyrexia
`
`Peripheral edema
`
`Asthenia
`
`Chills
`
`
`All Grades
`
` (%)
`
` 59
`
` 22
`
` 20
`
` 20
`
` 18
`
` 14
`
` 12
`
`47
`
` 22
`
`16
`
` 12
`
`12
`33
`
`24
`
`22
`
`14
`
`12
`
`
`
` Grade 3 or
`
` Higher (%)
`
`
` 4
`
` 2
`
` 2
`
` 0
`
` 2
`
` 0
`
` 0
`
`2
`
`6
`
`6
`
`10
`
`2
`6
`
`2
`
`0
`
`6
`
`0
`
`
`
`10
`
`

`

`
`
` Body System
`
`
` Skin and subcutaneous
`
` tissue disorders
`
`
`Respiratory, thoracic and
`
`mediastinal disorders
`
`Musculoskeletal and
` connective tissue disorders
`
`
`
`
`Nervous system disorders
`
`
`
`
`
` Adverse Reaction
`Bruising
`
`Rash
`
`Petechiae
`
`
`Cough
`
`Oropharyngeal pain
`
`Dyspnea
`Musculoskeletal pain
`
`Arthralgia
`
`Muscle spasms
`
`
`Dizziness
`
`Headache
` Decreased appetite
`
` Metabolism and nutrition
`
` disorders
` Neoplasms benign,
`
`
` malignant, unspecified
`
` Vascular disorders
` Hypertension
` †One patient death due to histiocytic sarcoma.
`
`
`
`
`
`Second malignancies
`
`
`
`
`All Grades
`
` (%)
`51
`
`25
`
`16
`
`
`22
`
`14
`
`12
`25
`
`24
`
`18
`
`
`20
`
`18
`
` 16
`
`10
`
`
`
`
` 16
`
`
` Grade 3 or
`
` Higher (%)
`
`2
`
`0
`
`0
`
`
`0
`
`0
`
`0
`6
`
`0
`
`2
`
`
`0
`
`2
`
` 2
`
`2†
`
`
`
`
` 8
`
` Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities
`
`
`
`
` in Patients with CLL/SLL (N=51) in Study 1102
`
`
`
`
`
`
`
`
` Percent of Patients (N=51)
`
`
`Grade 3 or 4 (%)
`All Grades (%)
`
`
`
`
`69
`12
`Platelets Decreased
`
`
`
`53
`26
`Neutrophils Decreased
`
`
`
`43
`Hemoglobin Decreased
`0
`
` * Based on laboratory measurements per IWCLL criteria and adverse reactions.
`
` Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.
`
`
` 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.
`
`
`
` 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
`
`
`Body System
`
`Adverse Reaction
`
`Gastrointestinal disorders
`
`
` IMBRUVICA
`
`(N=195)
` Grade 3 or
`
` All Grades
`
`
`
`(%)
` Higher (%)
`
`
`
`
`
` Ofatumumab
`
`(N=191)
`
` Grade 3 or
`
` All Grades
`
`
` Higher (%)
`(%)
`
`
`
`
`
`11
`
`Reference ID: 4462109
`
`

`

`
`
`
` IMBRUVICA
`
`(N=195)
` Grade 3 or
`
` All Grades
`
`
`
`(%)
` Higher (%)
`
`
`
`48
`4
`
`
`26
`2
`
`
`17
`1
`
`
`15
`0
`
`
`14
`0
`
`
`
`
` Ofatumumab
`
`(N=191)
`
` Grade 3 or
`
` All Grades
`
`
` Higher (%)
`(%)
`
`
`
`18
`2
`
`
`18
`0
`
`
`1
`6
`
`
`9
`0
`
`
`6
`1
`
`
`
`
`Body System
`
`Adverse Reaction
`
`Diarrhea
`
`Nausea
`
`Stomatitis*
`
`Constipation
`
`Vomiting
`General disorders and
`
`
`administration site conditions
`
`
`Pyrexia
`
`Infections and infestations
`
`
` Upper respiratory tract
`
`infection
`
`Pneumonia*
`
`Sinusitis*
`
` Urinary tract infection
`
` Skin and subcutaneous tissue
`
`
`disorders
`
`Rash*
`
`Petechiae
`
`Bruising*
`Musculoskeletal and
`
`connective tissue disorders
`
`Musculoskeletal pain*
`
`Arthralgia
`
`Nervous system disorders
`
`Headache
`
`Dizziness
` Injury, poisoning and
`
`
`procedural complications
`
`
`
`
`3
`0
`11
`Contusion
`
`
`
`
`Eye disorders
`
`
`
`
`3
`0
`10
`Vision blurred
`
`
`
`
` Subjects with multiple events for a given adverse reaction (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
`
`† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with
`
`
`
`
`
`
`
`
`
` a fatal outcome in the ofatumumab arm.
`
`
`
`
`
`24
`
`
`16
`
`
`15
`
`11
`
`10
`
`
`
`24
`
`14
`
`12
`
`
`
`28
`
`17
`
`
`14
`
`11
`
`
`
`2
`
`
`1
`
`
`12†
`
`1
`
`4
`
`
`
`3
`
`0
`
`0
`
`
`
`2
`
`1
`
`
`1
`
`0
`
`
`
`15
`
`
`11
`
`
`13
`
`6
`
`5
`
`
`
`13
`
`1
`
`1
`
`
`
`18
`
`7
`
`
`6
`
`5
`
`
`
`2†
`
`
`2†
`
`
`10†
`
`0
`
`1
`
`
`
`0
`
`0
`
`0
`
`
`
`1
`
`0
`
`
`0
`
`0
`
`
`
`0
`
`
`0
`
`
`
`Reference ID: 4462109
`
`
`12
`
`

`

`
`
`
`
` Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
`
`
` CLL/SLL in RESONATE
`
`
`
`
`
`
`
`
`Ofatumumab
`IMBRUVICA
`(N=191)
`(N=195)
`
`
`
` Grade 3 or 4
`
` All Grades
`
` All Grades
` Grade 3 or 4
`
`(%)
`(%)
`(%)
`(%)
`
`
`
`
`
` Neutrophils Decreased
`
`
` 57
` 26
`
`
` 51
` 23
`
` Platelets Decreased
`
` 45
`
` 10
`
` 52
`
` 5
` Hemoglobin Decreased
`
` 21
`
` 36
`
` 0
`
`
` 0
` Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia
`
`
`
`
`
` (8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.
`