` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`LABELING
`
`
`
`
`
`
`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--------------------------
`Indications and Usage (1.2)
`
`
`
` 1/14
`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).
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`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
`5.4
`Renal Toxicity
`Second Primary Malignancies
`5.5
`5.6
`Embryo-Fetal Toxicity
`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.
`
`Revised: 02/2014
`
`
`
`CYP3A Inhibitors
`7.1
`CYP3A Inducers
`7.2
`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
`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
`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. 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)].
`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. 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)].
`Infections
`5.2
`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.
`Second Primary Malignancies
`5.5
`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.
`5.6
`Embryo-Fetal Toxicity
`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)].
`
`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)]
`•
`• 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
`
`
`
`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
`
`All Grades (%)
`
`34
`14
`14
`14
`13
`41
`35
`18
`14
`30
`25
`11
`37
`14
`11
`27
`19
`11
`21
`12
`14
`13
`
`General disorders and
`administrative site
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`
`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
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Metabolism and nutrition
`disorders
`Nervous system disorders
`
`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.
`
`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
`
`Preferred Term
`
`All Grades (%)
`
`Gastrointestinal disorders
`
`Infections and infestations
`
`General disorders and
`administrative site conditions
`
`Skin and subcutaneous tissue
`disorders
`
`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
`
`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
`
`
`
`
`
`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
`
`Hypertension
`Vascular disorders
`*One patient death due to histiocytic sarcoma.
`
`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
`
`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.
`Nursing Mothers
`8.3
`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.
`Pediatric Use
`8.4
`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
`
`
`
`
`11
`DESCRIPTION
`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.
`
`12
`CLINICAL PHARMACOLOGY
`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
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`11
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`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.
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`12
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`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
`the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro.
`Coadministration of Ibrutinib with Substrates of Transporters
`In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp). Systemic
`ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1). However, it may
`have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral
`dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with
`IMBRUVICA may increase their blood concentration.
`
`NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenicity studies have not been conducted with ibrutinib.
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`13
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`Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a
`chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo
`bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
`Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology
`studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects
`on reproductive organs.
`
`CLINICAL STUDIES
`14
`14.1 Mantle Cell Lymphoma
`The safety and efficacy of IMBRUVICA in patients with MCL who have received at least one
`prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously
`treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92%
`were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1.
`The median time since diagnosis was 42 months, and median number of prior treatments was 3
`(range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of
`subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had
`extranodal involvement at screening.
`IMBRUVICA was administered orally at 560 mg once daily until disease progression or
`unacceptable toxicity. Tumor response was assessed according to the revised International
`Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in
`this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA
`are shown in Table 5.
`
`Table 5: Overall Response Rate (ORR) and Duration of Response (DOR) Based on
`Investigator Assessment in Patients with Mantle Cell Lymphoma
`
`Total (N=111)
`
`65.8
`ORR (%)
`95% CI (%)
`(56.2, 74.5)
`17.1
`CR (%)
`48.6
`PR (%)
`17.5 (15.8, NR)
`Median DOR months (95% CI)
`CI = confidence interval; CR = complete response; PR = partial response; NR = not reached
`
`An Independent Review Committee (IRC) performed independent reading and interpretation of
`imaging scans. The IRC review demonstrated an ORR of 69%.
`The median time to response was 1.9 months.
`Lymphocytosis
`Upon initiation of IMBRUVICA, a temporary increase in lymphocyte counts (i.e., ≥ 50%
`increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of
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`patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks
`of IMBRUVICA therapy and resolves by a median of 8 weeks.
`14.2 Chronic Lymphocyt