`
`
`
`
` 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.
`
`
` IMBRUVICATM (ibrutinib) capsules, for oral use
`
`
` Initial U.S. Approval: 2013
`
`
`
`
`
` ----------------------------RECENT MAJOR CHANGES--------------------------
`
` 1/14
`
`
`
`
`
`
`
`
` Indications and Usage (1.2)
`
`
`
`
` Dosage and Administration (2.2, 2.3)
`
`
`
`
` 1/14
`
`
`
`
` Warnings and Precautions (5.1, 5.2, 5.3, 5.4, and 5.5)
`
`
`
` 1/14
`
`
`
`
`
`
`
` ----------------------------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).
`
`
` • Chronic lymphocytic leukemia (CLL) who have received at least one
`
` prior therapy (1.2).
`
`
`
`
`
`
`
`
`
`
` These indications are based on overall response rate. Improvements in
`
`
`
`
`
` survival or disease-related symptoms have not been established (14.1, 14.2).
`
`
`
`
`
`
`
`
`
` -----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
` MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).
`
`
`
`
`
`
`
`
`
`
`
`
`
` CLL: 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
`------------------------WARNINGS AND PRECAUTIONS-----------------------
` • Hemorrhage: Monitor for bleeding (5.1).
`
`
`
`
`
`
` • Infections: Monitor patients for fever and infections and evaluate promptly
`
`
`
`
`
`
`
`
` (5.2).
`
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`
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`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
` INDICATIONS AND USAGE
` 1
`
` 1.1 Mantle Cell Lymphoma
`
`
`
`
`
`
` 1.2 Chronic Lymphocytic Leukemia
`
`
` 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 Missed Dose
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Hemorrhage
`
`
`
` 5.2
`
` Infections
`
` 5.3 Myelosuppression
` Renal Toxicity
`
` 5.4
`
`
` Second Primary Malignancies
`
`
`
` 5.5
` Embryo-Fetal Toxicity
`
` 5.6
`
`
` 6 ADVERSE REACTIONS
`
`
`
` 6.1 Mantle Cell Lymphoma
`
`
`
`
` 6.2
` Chronic Lymphocytic Leukemia
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`
`
` • Myelosuppression: Check complete blood counts monthly (5.3).
`
`
` • Renal Toxicity: Monitor renal function and maintain hydration (5.4).
`
`
`
`
`
`
`
`
`
` • Second Primary Malignancies: Other malignancies have occurred in
`
`
`
`
`
`
`
`
`
` patients, including skin cancers, and other carcinomas (5.5).
`
`
`
`
`
`
`
`
`
`
`
` • Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`
`
`
`
`
`
`
`
`
`
`
` potential risk to a fetus and to avoid pregnancy while taking the drug (5.6).
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------ADVERSE REACTIONS-------------------------------
`
`
` The most common adverse reactions (≥20%) in patients with MCL 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
`
`
`
`
`
`
`
`
`
` (6.1).
`
`
`
`
`
`
`
`
`
`
` The most common adverse reactions (≥20%) in patients with CLL were
`
`
` thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory
`
`
`
`
`
` tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation,
`
`
`
`
`
`
`
`
` peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (6.2).
`
`
`
`
`
`
`
`
`
` 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 baseline
`
`
`
`
`
`
`
`
`
`
`
` hepatic impairment (8.7).
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`
`
` approved patient labeling.
`
`
`
`
`
`
`
`
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`
`
`
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`
`
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`
`
`
`
` Revised: 02/2014
`
`
`
`
`
`
`
`
`
`
`
`
` CYP3A Inhibitors
`
` 7.1
`
` CYP3A Inducers
`
` 7.2
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
` Pregnancy
`
`
` 8.1
`
` 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
`
`
` 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
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
` * Sections or subsections omitted from the full prescribing information are
`
`
` not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`1
`
`
` INDICATIONS AND USAGE
`
` 1.1 Mantle Cell Lymphoma
`
`
` IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who
`
`
` have received at least one prior therapy. This indication is based on overall response rate. An
`
` improvement in survival or disease-related symptoms has not been established [see Clinical
`
`
`
` Studies (14.1)].
` Chronic Lymphocytic Leukemia
`
`
`
` 1.2
` IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`
`
`
`
` (CLL) who have received at least one prior therapy. This indication is based on overall response
` rate. An improvement in survival or disease-related symptoms has not been established [see
`
`
`
`
` Clinical Studies (14.2)].
`
`
`
`
`
`
`
` 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.
`
`
`
` Dosage
`2.2
`
`
`Mantle Cell Lymphoma
`
`
` The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once
`
` daily.
`
`
` Chronic Lymphocytic Leukemia
`
` The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once
`
` daily.
` Dose Modifications for Adverse Reactions
`
`
`
`2.3
`
`
`
`
` Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater
` neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of
`
`
`
` the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be
`
`
` reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per
`
`
`
`
` 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 for these toxicities are described below:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`

`

`
`
`
`
` 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 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, grapefruit products 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.
`
` 2.5 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
`
`
`
` CONTRAINDICATIONS
`
`4
`
` None
`
`
`
`
` WARNINGS AND PRECAUTIONS
`5
`
`
` 5.1 Hemorrhage
`
` Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding
`
`
`
`events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall,
`
`
`
` 3
`
`

`

`
`
`
`
`
`
`
` bleeding events including bruising of any grade occurred in 48% of patients with MCL treated
`
` with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.
`
`
` 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. At least 25% of patients
`
`
`
`
` with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common
` Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6.1) and (6.2)].
`
`
`
` Monitor patients for fever and infections and evaluate promptly.
` 5.3 Myelosuppression
`
`
` Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and
`
`35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and
`
`
`
`
`
`
`
` anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in
` patients with CLL.
`
`
` Monitor complete blood counts monthly.
` Renal Toxicity
`5.4
`
`
`Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-
`
` emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67%
`
`
`
` of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the
` upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL.
`
`
`
` Periodically monitor creatinine levels. Maintain hydration.
`5.5
`
` Second Primary Malignancies
`
` Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL
`
`
`
`
`
` who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers
`
`
`
`
`
` and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had
`
` other carcinomas.
` Embryo-Fetal Toxicity
`
`
` 5.6
`
` 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, 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`

`

`
` 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)]
`
`
`
`•
` • Myelosuppression [see Warnings and Precautions (5.3)]
`
`
` • Renal Toxicity [see Warnings and Precautions (5.4)]
`
`
` • Second Primary Malignancies [see Warnings and Precautions (5.5)]
`
`
`
`
`
` 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 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).
`
`
` The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
`
` abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
` 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
`
`
`
`
` Mantle Cell Lymphoma (N=111)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Preferred Term
`
`
`
` System Organ Class
` Gastrointestinal disorders Diarrhea
`
`
`
`
` Nausea
`
` Constipation
` Abdominal pain
`
`
`
` Vomiting
`
` Stomatitis
`
` Dyspepsia
`
`
`
`
`
`
` All Grades (%)
`
` 51
`
` 31
`
` 25
`
` 24
`
` 23
`
` 17
`
` 11
`
`
`
`
`
`
` Grade 3 or 4 (%)
` 5
`
`
` 0
`
` 0
`
` 5
`
` 0
`
` 1
`
` 0
`
`
`
` 5
`
`

`

`
` Preferred Term
`
`
`
`
`
` System Organ Class
`
` 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
`
`
`
`
`
` Metabolism and nutrition
`
` disorders
` Nervous system disorders
`
`
`
`
`
`
`
` General disorders and
`
` administrative site
`
`
` conditions
`
`
`
`
`
` Skin and subcutaneous
` tissue disorders
`
`
`
`
`
`
`
` Musculoskeletal and
` connective tissue disorders
`
`
`
`
`
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` All Grades (%)
`
`
` 34
`
` 14
`
` 14
`
` 14
`
` 13
`
` 41
`
` 35
`
` 18
`
` 14
`
` 30
`
` 25
`
` 11
`
` 37
`
` 14
`
` 11
`
` 27
`
` 19
`
` 11
`
` 21
`
` 12
`
` 14
`
` 13
`
`
`
` Grade 3 or 4 (%)
`
`
`
`
`
` 0
`
` 3
`
` 7
`
` 5
`
` 1
`
` 5
`
` 3
`
` 1
`
` 3
`
` 0
`
` 3
`
` 0
`
` 1
`
` 0
`
` 0
`
` 4
`
` 0
`
` 0
`
` 2
`
` 4
`
` 0
`
` 0
`
`
` Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
` in Patients with MCL (N=111)
`
`
`
`
`
`
`
`
`
`
` Platelets Decreased
`
`
` Neutrophils Decreased
`
`
` Hemoglobin Decreased
`
` * Based on laboratory measurements and adverse reactions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Percent of Patients (N=111)
`
`
`
`
`
`
` Grade 3 or 4 (%)
`
` All Grades (%)
`
`
`17
`57
`
`
`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.
`
`
`
`
`
`
`
`
` 6
`
`

`

`
` 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.
`
`
`
` 6.2
` Chronic Lymphocytic Leukemia
` The data described below reflect exposure to IMBRUVICA in a clinical trial that included
`
`
`
`
`
` 48 patients with previously treated CLL treated with 420 mg daily with a median treatment
` duration of 15.6 months.
`
`
`
` The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
`
`
`
` bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain,
`rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and
`
` dizziness (See Tables 3 and 4).
`The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
`
`
` hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.
` Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily
`
`
`
`
` occurring at a rate of ≥ 10% are presented in Table 3.
` Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`
`
`
`
`
` Chronic Lymphocytic Leukemia (N=48)
`
`
`
`
`
`
`
`
`
`
`
`
` System Organ Class
`
`
`
`
`
` Gastrointestinal disorders
`
`
`
`
`
` Diarrhea
`
`
` Constipation
`
` Nausea
`
` Stomatitis
`
` Vomiting
`
`
` Abdominal pain
`
` Dyspepsia
` Upper respiratory tract infection
`
` Sinusitis
`
` Skin infection
`
` Pneumonia
`
` Urinary tract infection
`
`
`
`
`
` General disorders and
`
` Fatigue
`
` administrative site conditions Pyrexia
`
`
`
` Peripheral edema
` Asthenia
`
`
` Chills
` Bruising
`
`
` Rash
` Petechiae
`
`
`
` Preferred Term
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` All Grades (%)
`
`
`
`
`
`
`
`
` 63
`
` 23
`
` 21
`
` 21
`
` 19
`
` 15
`
` 13
`
` 48
`
` 21
`
` 17
`
` 10
`
` 10
`
` 31
`
` 25
`
` 23
`
` 13
`
` 13
`
` 54
`
` 27
`
` 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
`
`
`
` 7
`
`
`
`
`
`
`
` Infections and infestations
`
`
`
` Skin and subcutaneous tissue
`
` disorders
`
`
`
`
`
`

`

`
`
`
`
` System Organ Class
`
`
`
`
`
` Preferred Term
`
`
`
` 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
`
`
` Injury, poisoning and
`
`
` procedural complications
`
`
`
`
`
` Psychiatric disorders
`
` Cough
`
` Oropharyngeal pain
`
` Dyspnea
`
`
`
`
`
` Musculoskeletal pain
`
` Arthralgia
` Muscle spasms
`
`
`
` Dizziness
`
` Headache
`
` Peripheral neuropathy
`
`
`
`
`
` Decreased appetite
`
`
`
` Second malignancies*
`
`
`
` Laceration
`
` Anxiety
`
` Insomnia
`
`
`
` 19
`
` 15
`
` 10
`
`
` 27
`
` 23
`
` 19
`
`
` 21
`
` 19
`
` 10
`
`
`
` 17
`
`
`
` 10*
`
`
`
` 10
`
`
` 10
`
` 10
`
`
`
` 17
`
`
` 0
`
` 0
`
` 0
`
`
` 6
`
` 0
`
` 2
`
`
` 0
`
` 2
`
` 0
`
`
`
` 2
`
`
`
` 0
`
`
`
` 2
`
`
` 0
`
` 0
`
`
`
` 8
`
`
` Hypertension
` Vascular disorders
`
`
` *One patient death due to histiocytic sarcoma.
`
`
`
` Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
`
`
`
`
` in Patients with CLL (N=48)
`
`
`
`
`
`
` Platelets Decreased
`
`
`
`
`Neutrophils Decreased
`
`
` Hemoglobin Decreased
`
`
`
`
` Percent of Patients (N=48)
`
`
`
`
`All Grades (%)
`
`
` Grade 3 or 4 (%)
`
`
`
`
`71
`
`
`54
`
`
`44
`
`
`10
`
`
`27
`
`
`0
`
` * Based on laboratory measurements per IWCLL criteria and adverse reactions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These
`
`
`
`
`
` included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse
`
`
`
` reactions leading to dose reduction occurred in 13% of patients.
`
`
`
`
`
` Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study
`
`including 4% with values above 10 mg/dL.
`
`
`
`
`7
`
`
`
` DRUG INTERACTIONS
`
`
`
` Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.
`
`
`
`Reference ID: 3452395
`
`
`
` 8
`
`

`

`
` CYP3A Inhibitors
`
`7.1
`
`
` In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased
` Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated
`
`
`
`
` in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single
`
`
`
`
`
` dose AUC values of 1445 ± 869 ng ⋅ hr/mL which is approximately 50% greater than steady state
`
` exposures seen at the highest indicated dose (560 mg).
`
` Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of
`
`
` CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for
`
`
` 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,
`telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use.
`
`
` Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must
` be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate
`
`
`
`
` CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see
`
`
` Dosage and Administration (2.4)].
`
`
` Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate
` inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].
`
`
` CYP3A Inducers
`7.2
`
`
` Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma
`
`
`
` concentrations by approximately 10-fold.
` 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 (5.6)].
`
`
` Risk Summary
` 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 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
`
`
`
`
`
`
`
`
`
` 9
`
`

`

`
` 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 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in
`
` effectiveness were observed between these patients and younger patients. A greater number of
`
`
` adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse
`
`
`
`
` events occurred more frequently among elderly patients (80% of patients 65 and older versus
`
`
` 61% of younger patients).
`
` Renal Impairment
`8.6
`
`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)].
`
`
` 8.7 Hepatic Impairment
`
`
`
`
`
` Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are
`
` expected in patients with hepatic impairment. Patients with serum aspartate transaminase
`
`
`
` (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were
`
` excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of
`
` IMBRUVICA in patients with baseline hepatic impairment [see 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 10
`
`

`

`
`
`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:
`
`O
`
`NH2
`
`N
`
`N
`
`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,
`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).
`
`Reference ID: 3452395
`
`
`
` 11
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` 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 increases ibrutinib exposure approximately 2-fold compared
`
`
` with administration after overnight fasting.
`
` Distribution
` Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no
`
`
`
` concentration dependence in the range of 50 to 1000 ng/mL. The apparent volume of distribution
` at steady state (Vd,ss/F) is approximately 10000 L.
`
`
`
`
` Metabolism
` Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites
`
`
`
`
` primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active
` metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK
`
`
` approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent
`
`
` ratio for PCI-45227 at steady-state is 1 to 2.8.
`
` Elimination
`
`
` Apparent clearance (CL/F) is approximately 1000 L/h. The half-life of ibrutinib is 4 to 6 hours.
` Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral
`
`
`
` administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of
`
`radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and
`
` less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of
`
`
`
`
` the radiolabeled excretion product in feces and none in urine, with the remainder of the dose
`
` being metabolites.
`
` Age
` Age (37 to 84 years) does not alter ibrutinib systemic clearance.
`
` Gender
`
` Gender does not alter ibrutinib systemic clearance.
`
` Renal Impairment
` Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the
`
`
`
`dose. Creatinine clearance > 25 mL/min had no influence on the exposure to IMBRUVICA.
`
` There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on
`
` dialysis.
`
`
`
`
`
`
`
`
`
`
`
` 12
`
`

`

`
` Hepatic Impairment
`
`
`
` Ibrutinib is metabolized in the liver. No clinical trials have been completed in subjects with
` impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic
`
`
`
` impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with
`
`
` moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in
`
`
`
` healthy volunteer trials.
`
` Drug Interactions
`
` Coadministration of Ibrutinib with CYP3A Inhibitors
`
`
` In a sequential design trial of 18 healthy volunteers, a single dose of 120 mg of IMBRUVICA
`
`
` was administered alone on Day 1 and a single dose of 40 mg of IMBRUVICA was administered
` on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 - 9). Ketoconazole
`
`
`
` increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively.
` Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that
`
`
` moderate CYP3A inhibitors (diltiazem and erythromycin) may increase the AUC of ibrutinib
`
`
` 6 to 9-fold in fasted condition.
` Coadministration of Ibrutinib with CYP3A Inducers
`
`
`
`
` Preliminary PK data from an ongoing dedicated drug interaction trial and simulations using
` PBPK indicate that rifampin (a strong CYP3A inducer) can decrease ibrutinib Cmax and AUC by
`
`
`
`
` more than 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer
`
`
`
` (efavirenz) may decrease the AUC of ibrutinib up to 3-fold.
` Coadministration of Ibrutinib with CYP Substrates
`
`
`
`
` In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227
`
` (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and