`
`
`
`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
`
`----------------------------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).
`
`This indication is based on overall response rate. An improvement in survival
`or disease-related symptoms has not been established (14.1).
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`560 mg taken orally once daily (four 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).
`• Myelosuppression: Check complete blood counts monthly (5.3).
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Dosing Guidelines
`
`2.2 Dosage for Mantle Cell Lymphoma
`
`
`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
`Infections
`5.2
`
`5.3 Myelosuppression
`
`Renal Toxicity
`5.4
`
`
`Second Primary Malignancies
`5.5
`Embryo-Fetal Toxicity
`5.6
`
`6 ADVERSE REACTIONS
`
`
`7 DRUG INTERACTIONS
`
`
`7.1
`CYP3A Inhibitors
`CYP3A Inducers
`7.2
`
`
`
`
`
`
`
`
`Reference ID: 3395788
`
`• 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).
`
`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: 11/2013
`
`
`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
`
`
`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
` 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)].
`
`
`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 for Mantle Cell Lymphoma
`The recommended dose of IMBRUVICA for MCL is 560 mg (four 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:
`
`Toxicity Occurrence
`
`MCL Dose Modification After Recovery
`Starting Dose = 560 mg
`
`First
`Second
`Third
`Fourth
`
`Restart at 560 mg daily
`Restart at 420 mg daily
`Restart at 280 mg daily
`Discontinue IMBRUVICA
`
`
`2.4
`Dose Modifications for Use with CYP3A Inhibitors
`
`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
`
`Reference ID: 3395788
`
`2
`
`

`

`
`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 had Grade 3 or higher bleeding events (subdural hematoma,
`gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any
`grade occurred in 48% of patients with MCL treated with 560 mg daily.
`
`The mechanism for the bleeding events is not well understood.
`Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies.
`
`Consider the benefit-risk of withholding ibrutinib 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 (14.1)].
`
`
`
`5.2
`Infections
`
`Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients
`with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse
`Events (CTCAE) [See Adverse Reactions (6)]. Monitor patients for fever and infections and
`evaluate promptly.
`
`Reference ID: 3395788
`
`3
`
`

`

`
`
`
` 5.3 Myelosuppression
`Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included
`neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts
`monthly.
`
`5.4
`Renal Toxicity
`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 and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically
`
`monitor creatinine levels. Maintain hydration.
`
`5.5
`Second Primary Malignancies
`
`Other malignancies (5%) have occurred in patients with MCL who have been treated with
`IMBRUVICA, including skin cancers (4%), and other carcinomas (1%).
`
`
`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 receiving the ibrutinib dose of 560 mg per day. 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)]
`
`•
`
`• 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.
`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.
`
`Reference ID: 3395788
`
`4
`
`

`

`
`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
`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
`
`nutritional disorders
`
`Nervous system disorders
`
`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
`
`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
`
`5
`
`Reference ID: 3395788
`
`

`

`
`
` 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 (%)
`
`
`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.
`
`
`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)].
`
`
`
`Reference ID: 3395788
`
`6
`
`

`

`
`
`
`
` 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
`administered the dose of 560 mg daily. 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.
`
`
`Reference ID: 3395788
`
`7
`
`

`

`
`
`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)].
`
`
`
`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.
`
`Reference ID: 3395788
`
`8
`
`

`

`
`
`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 observed in patients at
`560 mg is (mean ± standard deviation) 953 ± 705 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
`
`Reference ID: 3395788
`
`9
`
`

`

`
`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.
`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.
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`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.
`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 3.
`
`
`
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`Reference ID: 3395788
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`Table 3: 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 (%)
`
`
`(56.2, 74.5)
`95% CI (%)
`
`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
`patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks
`(median time 1.1 weeks) of IMBRUVICA therapy and resolves by a median of 8 weeks.
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`The white opaque 140 mg capsules marked with “ibr 140 mg” in black ink are available in white
`HDPE bottles with a child-resistant closure:
`
`• 90 capsules per bottle: NDC 57962-140-09
`
`• 120 capsules per bottle: NDC 57962-140-12
`
`Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted
`between 15°C and 30°C (59°F to 86°F). Retain in original package.
`
`
`PATIENT COUNSELING INFORMATION
`17
`See FDA-approved patient labeling (Patient Information)
`• Hemorrhage:
`
`
`Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in
`stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA
`may need to be interrupted for medical or dental procedures [see Warnings and Precautions
`(5.1)].
`Infections:
`
`Inform patients of the possibility of serious infection, and to report any signs or symptoms
`
`(fever, chills) suggestive of infection [see Warnings and Precautions (5.2)].
`
`•
`
`
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`•
`
`
`
`• Renal toxicity:
`
`Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate
`hydration [see Warnings and Precautions (5.4)].
`• Second primary malignancies:
`
`Inform patients that other malignancies have occurred in patients with MCL who have been
`treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and
`Precautions (5.5)].
`• Embryo-fetal toxicity:
`
`
`Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see
`
`Warnings and Precautions (5.6)].
`Inform patients to take IMBRUVICA orally once daily according to their physician’s
`instructions and that the capsules should be swallowed whole with a glass of water without
`being opened, broken, or chewed at approximately the same time each day [see Dosage and
`Administration (2.1)].
`• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken
`
`as soon as possible on the same day with a return to the normal schedule the following day.
`Patients should not take extra capsules to make up the missed dose [see Dosage and
`Administration (2.5)].
`• Advise patients of the common side effects associated with IMBRUVICA [see Adverse
`
`Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT
`INFORMATION.
`• Advise patients to inform their health care providers of all concomitant medications,
`
`including prescription medicines, over-the-counter drugs, vitamins, and herbal products
`[see Drug Interactions (7)].
`• Advise patients that they may experience loose stools or diarrhea, and should contact their
`
`doctor if their diarrhea persists.
`
`
`Active ingredient made in China.
`
`
`Distributed and Marketed by:
`
`Pharmacyclics, Inc.
`
`
`Sunnyvale, CA USA 94085
`
`and
`
`Marketed by:
`
`Janssen Biotech, Inc.
`
`Horsham, PA USA 19044
`
`
`
`Patent http://www.imbruvica.com
`
`
`IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc.
`
`
`
`©Pharmacyclics, Inc. 2013
`
`Issued: November 2013
`
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`Reference ID: 3395788
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` Patient Information
`
` IMBRUVICA (im-BRU-vih-kuh)
`(ibrutinib) capsules
`
`
`
`What is IMBRUVICA?
`
`IMBRUVICA is a prescription medicine used to treat people with mantle cell lymphoma (MCL) who have
`
`received at least one prior treatment.
`
`It is not known if IMBRUVICA is safe and effective in children.
`
`What should I tell my healthcare provider before taking IMBRUVICA?
`
`Before you take IMBRUVICA, tell your healthcare provider about all of your medical
`
`
`conditions, including if you:
`
`• have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for
`
`
`any planned medical, surgical, or dental procedure.
`• have bleeding problems
`
`• have liver problems
`
`
`• are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. You should not
`
`
`become pregnant while taking IMBRUVICA.
`
`• are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will
`
`take IMBRUVICA or breastfeed. You should not do both.
`Tell your healthcare provider about all the medicines you take, including prescription and over­
`the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other
`medicines may affect how IMBRUVICA works and can cause side effects.
`How should I take IMBRUVICA?
`• Take IMBRUVICA exactly as your healthcare provider tells you to take it.
`
`• Take IMBRUVICA 1 time a day.
`
`• Swallow IMBRUVICA capsules whole with a glass of water. Do not open, break, or chew IMBRUVICA
`
`capsules.
`• Take IMBRUVICA at about the same time each day.
`
`
`• If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next
`
`
`dose of IMBRUVICA at your regular time on the next day. Do not take 2 doses of IMBRUVICA on the
`
`
`
`same day to make up for a missed dose.
`What should I avoid while taking IMBRUVICA?
`
`● You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in
`
`
`
`
`marmalades) while you are taking IMBRUVICA. These products may increase the amount of
`
`
`IMBRUVICA in your blood.
`What are the possible side effects of IMBRUVICA?
`
`IMBRUVICA may cause serious side effects, including:
`• Bleedi