`These highlights do not include all the information needed to use
`IMBRUVICA safely and effectively. See full prescribing information for
`IMBRUVICA.
`IMBRUVICA® (ibrutinib) capsules, for oral use
`Initial U.S. Approval: 2013
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1.4)
`
`
`
`01/15
`Dosage and Administration (2.2, 2.3, 2.5)
`
`
`01/15
`Warnings and Precautions (5.1, 5.6)
`
`
`01/15
`----------------------------INDICATIONS AND USAGE---------------------------
`IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with:
`• Mantle cell lymphoma (MCL) who have received at least one prior
`therapy (1.1).
`Accelerated approval was granted for this indication based on overall
`response rate. Continued approval for this indication may be contingent
`upon verification of clinical benefit in confirmatory trials.
`• Chronic lymphocytic leukemia (CLL) who have received at least one
`prior therapy (1.2).
`• Chronic lymphocytic leukemia with 17p deletion (1.3).
`• Waldenström’s macroglobulinemia (WM) (1.4).
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).
`CLL and WM: 420 mg taken orally once daily (three 140 mg capsules once
`daily) (2.2).
`Capsules should be taken orally with a glass of water. Do not open, break, or
`chew the capsules (2.1).
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Capsule: 140 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Mantle Cell Lymphoma
`1.2 Chronic Lymphocytic Leukemia
`1.3
`Chronic Lymphocytic Leukemia with 17p deletion
`1.4 Waldenström's Macroglobulinemia
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`2.2 Dosage
`2.3 Dose Modifications for Adverse Reactions
`2.4 Dose Modifications for Use with CYP3A Inhibitors
`2.5 Dose Modifications for Use in Hepatic Impairment
`2.6 Missed Dose
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hemorrhage
`5.2
`Infections
`5.3 Cytopenias
`5.4 Atrial Fibrillation
`5.5
`Second Primary Malignancies
`Tumor Lysis Syndrome
`5.6
`5.7
`Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experiences
`6.2
`Postmarketing Experience
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`• Hemorrhage: Monitor for bleeding (5.1).
`• Infections: Monitor patients for fever and infections and evaluate promptly
`(5.2).
`• Cytopenias: Check complete blood counts monthly (5.3).
`• Atrial Fibrillation: Monitor patients for atrial fibrillation (5.4).
`• Second Primary Malignancies: Other malignancies have occurred in
`patients, including skin cancers, and other carcinomas (5.5).
`• Tumor Lysis Syndrome (TLS): Monitor patients at risk for TLS (e.g. high
`tumor burden) (5.6).
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`potential risk to a fetus and to avoid pregnancy while taking the drug (5.7).
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions (≥25%) in patients with B-cell
`malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia,
`diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper
`respiratory tract infection, and rash.
`To report SUSPECTED ADVERSE REACTIONS, contact
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------------
`CYP3A Inhibitors: Avoid co-administration with strong and moderate CYP3A
`inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA
`dose (2.4, 7.1).
`CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2).
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Hepatic Impairment: Avoid use of IMBRUVICA in patients with moderate or
`severe baseline hepatic impairment. In patients with mild impairment, reduce
`IMBRUVICA dose (8.7).
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 01/2015
`
`
`
`7 DRUG INTERACTIONS
`7.1 CYP3A Inhibitors
`7.2 CYP3A Inducers
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8
`Females and Males of Reproductive Potential
`Plasmapheresis
`8.9
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Mantle Cell Lymphoma
`14.2 Chronic Lymphocytic Leukemia
`14.3 Waldenström's Macroglobulinemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`
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`Coalition for Affordable Drugs IV LLC v. Pharmacyclics LLC
`Case IPR2015-01076
`
`
`
`
`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`1.1 Mantle Cell Lymphoma
`IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who
`have received at least one prior therapy.
`Accelerated approval was granted for this indication based on overall response rate. Continued
`approval for this indication may be contingent upon verification of clinical benefit in
`confirmatory trials [see Clinical Studies (14.1)].
`1.2
`Chronic Lymphocytic Leukemia
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL) who have received at least one prior therapy [see Clinical Studies (14.2)].
`1.3 Chronic Lymphocytic Leukemia with 17p deletion
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL) with 17p deletion [see Clinical Studies (14.2)].
`1.4 Waldenström’s Macroglobulinemia
`IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia
`(WM) [see Clinical Studies (14.3)].
`
`DOSAGE AND ADMINISTRATION
`2
`Dosing Guidelines
`2.1
`Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow
`the capsules whole with water. Do not open, break, or chew the capsules.
`2.2
`Dosage
`Mantle Cell Lymphoma
`The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once
`daily.
`Chronic Lymphocytic Leukemia and Waldenström’s Macroglobulinemia
`The recommended dose of IMBRUVICA for CLL and WM is 420 mg (three 140 mg capsules)
`orally once daily.
`2.3
`Dose Modifications for Adverse Reactions
`Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater
`neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of
`the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be
`reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per
`
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`day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities
`persist or recur following two dose reductions, discontinue IMBRUVICA.
`Recommended dose modifications are described below:
`
`Toxicity Occurrence
`First
`Second
`Third
`Fourth
`
`MCL Dose Modification After
`Recovery
`Starting Dose = 560 mg
`Restart at 560 mg daily
`Restart at 420 mg daily
`Restart at 280 mg daily
`Discontinue IMBRUVICA
`
`CLL and WM Dose
`Modification After Recovery
`Starting Dose = 420 mg
`Restart at 420 mg daily
`Restart at 280 mg daily
`Restart at 140 mg daily
`Discontinue IMBRUVICA
`
`Dose Modifications for Use with CYP3A Inhibitors
`2.4
`Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative
`agents with less CYP3A inhibition.
`Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir,
`indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For
`short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and
`antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer
`needed [see Drug Interactions (7.1)].
`Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g.,
`fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir,
`crizotinib, imatinib, verapamil, and ciprofloxacin) [see Drug Interactions (7.1)].
`Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more
`closely for signs of IMBRUVICA toxicity.
`
`Dose Modifications for Use in Hepatic Impairment
`2.5
`For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg
`daily (one capsule). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic
`impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.7) and Clinical
`Pharmacology (12.3)].
`2.6 Missed Dose
`If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
`on the same day with a return to the normal schedule the following day. Extra capsules of
`IMBRUVICA should not be taken to make up for the missed dose.
`
`DOSAGE FORMS AND STRENGTHS
`3
`140 mg capsules
`
`3
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`CONTRAINDICATIONS
`
` 4
`
`
`None
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Hemorrhage
`Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher
`bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural
`hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including
`bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
`The mechanism for the bleeding events is not well understood.
`IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or
`anticoagulant therapies.
`Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-
`surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
`5.2
`Infections
`Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater
`infections occurred in 14% to 26% of patients. [See Adverse Reactions (6.1)]. Cases of
`progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with
`IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.
`5.3
`Cytopenias
`Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%),
`thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated
`with IMBRUVICA.
`Monitor complete blood counts monthly.
`5.4
`Atrial Fibrillation
`Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with
`IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous
`history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients
`who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea
`should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of
`IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3)].
`5.5
`Second Primary Malignancies
`Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have
`occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy
`was non-melanoma skin cancer (range, 4 to 11 %).
`
`4
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`Tumor Lysis Syndrome
`5.6
`Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely
`and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor
`burden).
`
`Embryo-Fetal Toxicity
`5.7
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in
`patients with MCL and 20 times those reported in patients with CLL or WM, receiving the
`ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were
`observed at lower exposures. Advise women to avoid becoming pregnant while taking
`IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while
`taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in
`Specific Populations (8.1)].
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in more detail in other sections of the labeling:
`• Hemorrhage [see Warnings and Precautions (5.1)]
`Infections [see Warnings and Precautions (5.2)]
`•
`• Cytopenias [see Warnings and Precautions (5.3)]
`• Atrial Fibrillation [see Warnings and Precautions (5.4)]
`• Second Primary Malignancies [see Warnings and Precautions (5.5)]
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
`Because clinical trials are conducted under widely variable conditions, adverse event rates
`observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`another drug and may not reflect the rates observed in practice.
`6.1
`Clinical Trials Experience
`Mantle Cell Lymphoma
`The data described below reflect exposure to IMBRUVICA in a clinical trial that included
`111 patients with previously treated MCL treated with 560 mg daily with a median treatment
`duration of 8.3 months.
`The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
`neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract
`infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased
`appetite (see Tables 1 and 2).
`
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`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.
`
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`Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`MCL (N=111)
`
`Grade 3 or 4 (%)
`5
`0
`0
`5
`0
`1
`0
`
` 0
`
`
`3
`7
`5
`1
`5
`3
`1
`3
`0
`3
`0
`1
`0
`0
`4
`0
`0
`2
`4
`0
`0
`
`7
`
`All Grades (%)
`51
`31
`25
`24
`23
`17
`11
`
`34
`14
`14
`14
`13
`41
`35
`18
`14
`30
`25
`11
`37
`14
`11
`27
`19
`11
`21
`12
`14
`13
`
`Preferred Term
`System Organ Class
`Gastrointestinal disorders Diarrhea
`Nausea
`Constipation
`Abdominal pain
`Vomiting
`Stomatitis
`Dyspepsia
`Infections and infestations Upper respiratory tract
`infection
`Urinary tract infection
`Pneumonia
`Skin infections
`Sinusitis
`Fatigue
`Peripheral edema
`Pyrexia
`Asthenia
`Bruising
`Rash
`Petechiae
`Musculoskeletal pain
`Muscle spasms
`Arthralgia
`Dyspnea
`Cough
`Epistaxis
`Decreased appetite
`Dehydration
`Dizziness
`Headache
`
`General disorders and
`administrative site
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Metabolism and nutrition
`disorders
`Nervous system disorders
`
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`Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with MCL (N=111)
`
`
`
`
`
`Platelets Decreased
`Neutrophils Decreased
`Hemoglobin Decreased
`* Based on laboratory measurements and adverse reactions
`
`Percent of Patients (N=111)
`All Grades (%)
`Grade 3 or 4 (%)
`57
`17
`47
`29
`41
`9
`
`Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most
`frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).
`Adverse reactions leading to dose reduction occurred in 14% of patients.
`Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed
`intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases
`were in the setting of disease progression.
`Forty percent of patients had elevated uric acid levels on study including 13% with values above
`10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.
`
`Chronic Lymphocytic Leukemia
`The data described below reflect exposure to IMBRUVICA in an open label clinical trial
`(Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial
`(Study 2) that included 391 randomized patients with previously treated CLL or SLL.
`The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were
`thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper
`respiratory tract infection, rash, nausea, and pyrexia.
`
`Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2
`discontinued treatment due to adverse events. These included infections, subdural hematomas
`and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of
`patients.
`Study 1
`Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent
`IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.
`
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`Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`CLL (N=48) in Study 1
`
`System Organ Class
`Gastrointestinal disorders
`
`Infections and infestations
`
`General disorders and
`administrative site conditions
`
`Skin and subcutaneous tissue
`disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Nervous system disorders
`
`Preferred Term
`Diarrhea
`Constipation
`Nausea
`Stomatitis
`Vomiting
`Abdominal pain
`Dyspepsia
`Upper respiratory tract infection
`Sinusitis
`Skin infection
`Pneumonia
`Urinary tract infection
`Fatigue
`Pyrexia
`Peripheral edema
`Asthenia
`Chills
`Bruising
`Rash
`Petechiae
`Cough
`Oropharyngeal pain
`Dyspnea
`Musculoskeletal pain
`Arthralgia
`Muscle spasms
`Dizziness
`Headache
`Peripheral neuropathy
`Decreased appetite
`
`Second malignancies*
`
`Laceration
`
`Metabolism and nutrition
`disorders
`Neoplasms benign,
`malignant, unspecified
`Injury, poisoning and
`procedural complications
`Psychiatric disorders
`
`Anxiety
`Insomnia
`Hypertension
`Vascular disorders
`*One patient death due to histiocytic sarcoma.
`
`All Grades (%)
`63
`23
`21
`21
`19
`15
`13
`48
`21
`17
`10
`10
`31
`25
`23
`13
`13
`54
`27
`17
`19
`15
`10
`27
`23
`19
`21
`19
`10
`17
`
`10*
`
`10
`
`10
`10
`17
`
`Grade 3 or 4
`(%)
`4
`2
`2
`0
`2
`0
`0
`2
`6
`6
`8
`0
`4
`2
`0
`4
`0
`2
`0
`0
`0
`0
`0
`6
`0
`2
`0
`2
`0
`2
`
`0
`
`2
`
`0
`0
`8
`
`9
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`Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with CLL (N=48) in Study 1
`
`
`
`Percent of Patients (N=48)
`All Grades (%)
`Grade 3 or 4 (%)
`71
`10
`Platelets Decreased
`54
`27
`Neutrophils Decreased
`44
`0
`Hemoglobin Decreased
`* Based on laboratory measurements per IWCLL criteria and adverse reactions
`
`Study 2
`Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect
`exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
`with a median of 5.3 months in Study 2.
`
`Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2
`
`System Organ Class
`ADR Term
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Stomatitis*
`Constipation
`Vomiting
`General disorders and
`administration site conditions
`Fatigue
`Pyrexia
`Infections and infestations
`Upper respiratory tract
`infection
`Pneumonia*
`Sinusitis*
`Urinary tract infection
`Skin and subcutaneous tissue
`disorders
`Rash*
`Petechiae
`Bruising*
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`48
`4
`26
`2
`17
`1
`15
`0
`14
`0
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`18
`2
`18
`0
`6
`1
`9
`0
`6
`1
`
`
`
`28
`24
`
`16
`
`15
`11
`10
`
`
`24
`14
`12
`
`2
`2
`
`1
`
`10
`1
`4
`
`
`3
`0
`0
`
`30
`15
`
`11
`
`13
`6
`5
`
`
`13
`1
`1
`
`2
`1
`
`2
`
`9
`0
`1
`
`
`0
`0
`0
`
`10
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`
`
`System Organ Class
`ADR Term
`Musculoskeletal and
`connective tissue disorders
`Musculoskeletal Pain*
`Arthralgia
`Nervous system disorders
`Headache
`Dizziness
`Injury, poisoning and
`procedural complications
`Contusion
`Eye disorders
`Vision blurred
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`
`
`28
`17
`
`14
`11
`
`
`11
`
`10
`
`2
`1
`
`1
`0
`
`
`0
`
`0
`
`18
`7
`
`6
`5
`
`
`3
`
`3
`
`1
`0
`
`0
`0
`
`
`0
`
`0
`
`Subjects with multiple events for a given ADR term are counted once only for each ADR term.
`The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
`* Includes multiple ADR terms
`
`
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`57
`26
`45
`10
`21
`0
`
`Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Study 2
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`51
`23
`Neutrophils Decreased
`52
`5
`Platelets Decreased
`36
`0
`Hemoglobin Decreased
`* Based on laboratory measurements per IWCLL criteria
`
`Waldenström’s Macroglobulinemia
`The data described below reflect exposure to IMBRUVICA in an open label clinical trial that
`included 63 patients with previously treated WM.
`The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia,
`thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
`Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to
`adverse events. Adverse events leading to dose reduction occurred in 11% of patients.
`Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect
`exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.
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`Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`Waldenström’s Macroglobulinemia (N=63)
`
`Preferred Term
`Diarrhea
`Nausea
`Stomatitis*
`Gastroesophageal reflux disease
`Rash*
`Bruising*
`Pruritus
`Fatigue
`
`All Grades
`(%)
`37
`21
`16
`13
`22
`16
`11
`21
`
`Grade 3 or 4
`(%)
`0
`0
`0
`0
`0
`0
`0
`0
`
`System Organ Class
`Gastrointestinal disorders
`
`Skin and subcutaneous tissue
`disorders
`
`General disorders and
`administrative site conditions
`Musculoskeletal and
`connective tissue disorders
`Infections and infestations
`
`Respiratory, thoracic and
`mediastinal disorders
`Nervous system disorders
`
`Muscle spasms
`Arthropathy
`Upper respiratory tract infection
`Sinusitis
`Pneumonia*
`Skin infection*
`Epistaxis
`Cough
`Dizziness
`Headache
`Skin cancer*
`
`21
`13
`19
`19
`14
`14
`19
`13
`14
`13
`11
`
`0
`0
`0
`0
`6
`2
`0
`0
`0
`0
`0
`
`Neoplasms benign,
`malignant, and unspecified
`(including cysts and polyps)
`The system organ class and individual ADR terms are sorted in descending frequency order.
`* Includes multiple ADR terms.
`
`
`Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with WM (N=63)
`
`
`
`
`Platelets Decreased
`Neutrophils Decreased
`Hemoglobin Decreased
`* Based on laboratory measurements.
`
`Percent of Patients (N=63)
`All Grades (%)
`Grade 3 or 4 (%)
`43
`13
`44
`19
`13
`8
`
`6. 2 Postmarketing Experience
`The following adverse reactions have been identified during post-approval use of IMBRUVICA.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
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`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have
`been reported.
`
`DRUG INTERACTIONS
`7
`Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.
`7.1
`CYP3A Inhibitors
`In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased
`Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated
`in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single
`dose AUC values of 1445 ± 869 ng ⋅ hr/mL which is approximately 50% greater than steady state
`exposures seen at the highest indicated dose (560 mg).
`Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of
`CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for
`7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,
`telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use.
`Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must
`be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate
`CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see
`Dosage and Administration (2.4)].
`Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate
`inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].
`7.2
`CYP3A Inducers
`Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib
`Cmax and AUC by approximately 13- and 10-fold, respectively.
`Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and
`St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical
`Pharmacology (12.3)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Category D [see Warnings and Precautions (5.7)].
`Risk Summary
`
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`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant
`while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.
`Animal Data
`Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral
`doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with
`visceral malformations (heart and major vessels) and increased post-implantation loss. The dose
`of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL
`and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily
`and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with
`decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the
`exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
`8.3
`Nursing Mothers
`It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in
`human milk and because of the potential for serious adverse reactions in nursing infants from
`IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the
`drug, taking into account the importance of the drug to the mother.
`8.4
`Pediatric Use
`The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.
`8.5 Geriatric Use
`Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences
`in effectiveness were observed between these patients and younger patients. Cardiac adverse
`events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and
`gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly
`patients.
`Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences
`in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred
`more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65
`versus 51% of younger patients) [see Clinical Studies (14.2)].
`Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in
`effectiveness were observed between these patients and younger patients. Cardiac adverse events
`(atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection)
`occurred more frequently among elderly patients.
`8.6
`Renal Impairment
`Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with
`Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal
`impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)].
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`8.7 Hepatic Impairment
`Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in
`ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-,
`8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and
`severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function.
`The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment.
`Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as
`needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe
`hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and
`Clinical Pharmacology (12.3)].
`8.8
`Females and Males of Reproductive Potential
`Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA
`can cause fetal harm [see Use in Specific Populations (8.1)].
`8.9
`Plasmapheresis
`Management of hyperviscosity in patients with WM may include plasmapheresis before and
`during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
`
`
`DESCRIPTION
`11
`Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It is a white to off-white solid with
`the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble
`in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.
`The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-
`pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:
`
`NH2
`
`N
`
`N
`
`O
`
`N
`
`N
`
`(R)
`
`N
`
`O
`
`
`
`IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules
`that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following
`inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose,
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`sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each
`white opaque capsule is marked with “ibr 140 mg” in black ink.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine
`residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a
`signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s
`role in signaling through the B-cell surface receptors results in activation of pathways necessary
`for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits
`malignant B-cell proliferation and survival in vivo as well as cell migration and substrate
`adhesion in vitro.
`12.2 Pharmacodynamics
`In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in
`peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of
`≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).
`12.3 Pharmacokinetics
`Absorption
`Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib
`exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation)
`observed in patients at 560 mg is 953 ± 705 ng⋅h/mL and in patients at 420 mg is
`680 ± 517 ng⋅h/mL. Administration with food increased ibrutinib Cmax and AUC by
`approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after
`overnight fasting.
`Distribution