Ibrutinib 140 MG Oral Capsule [Imbruvica]

Details

Generic Name: IBRUTINIB

Brand Name: IMBRUVICA

Substance Name(s):
IBRUTINIB

DRUG INTERACTIONS

7 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).

7.1 CYP3A Inhibitors Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A).

In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively.

The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ∙ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A.

For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use.

Avoid strong CYP3A inhibitors that are needed chronically.

If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4)].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

7.2 CYP3A Inducers Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St.

John’s Wort).

Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 There is no specific experience in the management of ibrutinib overdose in patients.

One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg.

Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.

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: 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.

Chemical Structure

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 13.

Table 13: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL Total (N=111) CI = confidence interval; CR = complete response; PR = partial response; NR = not reached ORR (%) 65.8 95% CI (%) (56.2, 74.5) CR (%) 17.1 PR (%) 48.6 Median DOR months (95% CI) 17.5 (15.8, NR) 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 of IMBRUVICA therapy and resolves by a median of 8 weeks.

14.2 Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one uncontrolled trial and three randomized, controlled trials.

Study 1 An open-label, multi-center trial was conducted in 48 previously treated CLL patients.

The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian.

All patients had a baseline ECOG performance status of 0 or 1.

The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments).

At baseline, 46% of subjects had at least one tumor ≥ 5 cm.

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity.

The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee.

The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses.

None of the patients achieved a complete response.

The DOR ranged from 5.6 to 24.2+ months.

The median DOR was not reached.

Study 2 A randomized, multi-center, open-label Phase 3 study of IMBRUVICA versus ofatumumab was conducted in patients with previously treated CLL or SLL.

Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses.

Fifty seven patients randomized to ofatumumab crossed over following progression to receive IMBRUVICA.

The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian.

All patients had a baseline ECOG performance status of 0 or 1.

The trial enrolled 373 patients with CLL and 18 patients with SLL.

The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments).

At baseline, 58% of patients had at least one tumor ≥ 5 cm.

Thirty-two percent of patients had 17p deletion.

Efficacy results for Study 2 are shown in Table 14 and the Kaplan-Meier curves for PFS, assessed by an IRC according to IWCLL criteria, and OS are shown in Figures 1 and 2, respectively.

Table 14: Efficacy Results in Patients with CLL/SLL in Study 2 Endpoint IMBRUVICA N=195 Ofatumumab N=196 CI = confidence interval; HR = hazard ratio; NR = not reached Progression Free SurvivalIRC evaluated.

All partial responses achieved; none of the patients achieved a complete response.

Number of events (%) 35 (17.9) 111 (56.6) Disease progression 26 93 Death events 9 18 Median (95% CI), months NR 8.1 (7.2, 8.3) HR (95% CI) 0.22 (0.15, 0.32) Overall SurvivalMedian OS not reached for either arm Number of deaths (%) 16 (8.2) 33 (16.8) HR (95% CI) 0.43 (0.24, 0.79) Overall Response Rate 42.6% 4.1% Figure 1: Kaplan-Meier Curve of Progression Free Survival (ITT Population) in Patients with CLL/SLL in Study 2 Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with CLL/SLL in Study 2 Figure 1 Figure 2 CLL/SLL with 17p deletion (del 17p CLL/SLL) in Study 2 Study 2 included 127 patients with del 17p CLL/SLL.

The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian.

All patients had a baseline ECOG performance status of 0 or 1.

PFS and ORR were assessed by an IRC.

Efficacy results for del 17p CLL/SLL are shown in Table 15.

Table 15: Efficacy Results in Patients with del 17p CLL/SLL in Study 2 Endpoint IMBRUVICA N=63 Ofatumumab N=64 CI = confidence interval; HR = hazard ratio; NR = not reached Progression Free SurvivalIRC evaluated.

All partial responses achieved; none of the patients achieved a complete response.

Number of events (%) 16 (25.4) 38 (59.4) Disease progression 12 31 Death events 4 7 Median (95% CI), months NR 5.8 (5.3, 7.9) HR (95% CI) 0.25 (0.14, 0.45) Overall Response Rate 47.6% 4.7% Study 3 A randomized, multi-center, open-label study of IMBRUVICA versus chlorambucil was conducted in patients with treatment naïve CLL or SLL who were 65 years of age or older.

Patients (n = 269) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.

The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian.

Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an ECOG performance status of 2.

The trial enrolled 249 patients with CLL and 20 patients with SLL.

At baseline, 20% of patients had 11q deletion.

The most common reasons for initiating CLL therapy include: progressive marrow failure demonstrated by anemia and/or thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).

With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and 21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively].

With 41% of patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and 2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)] in the IMBRUVICA and chlorambucil arms, respectively.

Efficacy results for Study 3 are shown in Table 16 and the Kaplan-Meier curve for PFS, assessed by an IRC according to IWCLL criteria is shown in Figure 3.

Table 16: Efficacy Results in Patients with CLL/SLL in Study 3 Endpoint IMBRUVICA N=136 Chlorambucil N=133 Progression Free SurvivalIRC evaluated; Five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved complete response Number of events (%) 15 (11.0) 64 (48.1) Disease progression 12 57 Death events 3 7 Median (95% CI), months NR 18.9 (14.1, 22.0) HRHR = hazard ratio; NR = not reached (95% CI) 0.16 (0.09, 0.28) Overall Response Rate (CR + PR) 82.4% 35.3% P-value <0.0001 Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in Study 3 Figure 3 Study 4 A randomized, multicenter, double-blinded Phase 3 study of IMBRUVICA in combination with bendamustine and rituximab (BR) versus placebo + BR was conducted in patients with previously treated CLL or SLL.

Patients (n = 578) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity.

All patients received BR for a maximum of six 28-day cycles.

Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles.

Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles 2 through 6, Day 1.

The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian.

All patients had a baseline ECOG performance status of 0 or 1.

The median time since diagnosis was 5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments).

At baseline, 56% of patients had at least one tumor ≥ 5 cm and 26% presented with del11q.

Efficacy results for Study 4 are shown in Table 17 and the Kaplan-Meier curves for PFS are shown in Figure 4.

Table 17: Efficacy Results Patients with CLL/SLL in Study 4 Endpoint IMBRUVICA + BR N=289 Placebo + BR N=289 BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio Progression Free SurvivalIRC evaluated, Twenty four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm achieved complete response Number of events (%) 56 (19.4) 183 (63.3) Median (95% CI), months Not reached 13.3 (11.3, 13.9) HR (95% CI) 0.20 (0.15, 0.28) Overall Response Rate 82.7% 67.8% Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in Study 4 Figure 4 Lymphocytosis Upon initiation of IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of patients in the CLL studies.

The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks).

When IMBRUVICA was administered with chemoimmunotherapy, lymphocytosis was 7% with IMBRUVICA + BR versus 6% with placebo + BR.

14.3 Waldenström’s Macroglobulinemia The safety and efficacy of IMBRUVICA in WM were evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients.

The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian.

All patients had a baseline ECOG performance status of 0 or 1.

The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments).

At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity.

The responses were assessed by investigators and an Independent Review Committee (IRC) using criteria adopted from the International Workshop of Waldenström’s Macroglobulinemia.

Responses, defined as partial response or better, per IRC are shown in Table 18.

Table 18: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with WM in study 5 Total (N=63) CI = confidence interval; NR = not reached Response rate (CR+VGPR+PR), (%) 61.9 95% CI (%) (48.8, 73.9) Complete Response (CR) 0 Very Good Partial Response (VGPR), (%) 11.1 Partial Response (PR), (%) 50.8 Median duration of response, months (range) NR (2.8+, 18.8+) The median time to response was 1.2 months (range, 0.7-13.4 months).

14.4 Marginal Zone Lymphoma The safety and efficacy of IMBRUVICA in MZL were evaluated in an open-label, multi-center, single-arm trial of patients who received at least one prior therapy.

The efficacy analysis included 63 patients with 3 sub-types of MZL: mucosa-associated lymphoid tissue (MALT; N=32), nodal (N=17), and splenic (N=14).

The median age was 66 years (range, 30 to 92 years), 59% were female, and 84% were Caucasian.

Ninety two percent of patients had a baseline ECOG performance status of 0 or 1 and 8% had ECOG performance status 2.

The median time since diagnosis was 3.8 years, and the median number of prior treatments was 2 (range, 1 to 9 treatments).

IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity.

The responses were assessed by investigators and an IRC using criteria adopted from the International Working Group criteria for malignant lymphoma.

Responses per IRC are shown in Table 19.

Table 19: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with MZL in Study 6 Total (N=63) CI = confidence interval; NR = not reached Median follow-up time on study = 19.4 months Response rate (CR+PR), (%) 46.0% 95% CI (%) (33.4, 59.1) Complete Response (CR), (%) 3.2 Partial Response (PR), (%) 42.9 Median duration of response, months (range) NR (16.7, NR) The median time to response was 4.5 months (range, 2.3 to 16.4 months).

Overall response rates were 46.9%, 41.2%, and 50.0% for the 3 MZL sub-types (MALT, nodal, splenic), respectively.

HOW SUPPLIED

14.4 Marginal Zone Lymphoma The safety and efficacy of IMBRUVICA in MZL were evaluated in an open-label, multi-center, single-arm trial of patients who received at least one prior therapy.

The efficacy analysis included 63 patients with 3 sub-types of MZL: mucosa-associated lymphoid tissue (MALT; N=32), nodal (N=17), and splenic (N=14).

The median age was 66 years (range, 30 to 92 years), 59% were female, and 84% were Caucasian.

Ninety two percent of patients had a baseline ECOG performance status of 0 or 1 and 8% had ECOG performance status 2.

The median time since diagnosis was 3.8 years, and the median number of prior treatments was 2 (range, 1 to 9 treatments).

IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity.

The responses were assessed by investigators and an IRC using criteria adopted from the International Working Group criteria for malignant lymphoma.

Responses per IRC are shown in Table 19.

Overall response rates were 46.9%, 41.2%, and 50.0% for the 3 MZL sub-types (MALT, nodal, splenic), respectively.

RECENT MAJOR CHANGES

Indications and Usage (1.2, 1.3, 1.5) 01/2017 Dosage and Administration (2.2) 01/2017 Warnings and Precautions (5) 3/2016

GERIATRIC USE

8.5 Geriatric Use Of the 905 patients in clinical studies of IMBRUVICA, 62% were ≥ 65 years of age, while 21% were ≥75 years of age.

No overall differences in effectiveness were observed between younger and older patients.

Anemia (all grades) and Grade 3 or higher pneumonia occurred more frequently among older patients treated with IMBRUVICA.

DOSAGE FORMS AND STRENGTHS

3 140 mg capsules Capsule: 140 mg (3)

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

1 IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1).

Accelerated approval was granted for this indication based on overall response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) (1.2).

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion (1.3).

Waldenström’s macroglobulinemia (WM) (1.4).

Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy (1.5).

Accelerated approval was granted for this indication based on overall response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.1 Mantle Cell Lymphoma IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial [see Clinical Studies (14.1)].

1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) [see Clinical Studies (14.2)].

1.3 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion [see Clinical Studies (14.2)].

1.4 Waldenström’s Macroglobulinemia IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3)].

1.5 Marginal Zone Lymphoma IMBRUVICA is indicated for the treatment of patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.

Accelerated approval was granted for this indication based on overall response rate [see Clinical Studies (14.4)].

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

PREGNANCY

8.1 Pregnancy Risk Summary IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies.

In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including malformations [see Data].

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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at 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 resorptions and post-implantation loss.

The dose of 80 mg/kg/day in rats is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively.

Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights.

The dose of 40 mg/kg/day in rats is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day.

Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss.

The dose of 15 mg/kg/day in rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hemorrhage: Monitor for bleeding and manage (5.1).

Infections: Monitor patients for fever and infections, evaluate promptly, and treat (5.2).

Cytopenias: Check complete blood counts monthly (5.3).

Atrial Fibrillation: Monitor for atrial fibrillation and manage (5.4).

Hypertension: Monitor blood pressure and treat (5.5).

Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.6).

Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.

Monitor and treat for TLS (5.7).

Embryo-Fetal Toxicity: Can cause fetal harm.

Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug and for 1 month after cessation of therapy.

Advise men to avoid fathering a child during the same time period (5.8, 8.3).

5.1 Hemorrhage Fatal bleeding events have occurred in patients treated with IMBRUVICA.

Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in up to 6% of patients.

Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].

5.2 Infections Fatal and non-fatal infections have occurred with IMBRUVICA therapy.

Grade 3 or greater infections occurred in 14% to 29% of patients [see Adverse Reactions (6.1), (6.2)].

Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA.

Evaluate patients for fever and infections and treat appropriately.

5.3 Cytopenias Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

5.4 Atrial Fibrillation Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation.

Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed.

Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and Administration (2.3)].

5.5 Hypertension Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months).

Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

5.6 Second Primary Malignancies Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA.

The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

5.7 Tumor Lysis Syndrome Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy.

Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

5.8 Embryo-Fetal Toxicity Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman.

Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryofetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with hematologic malignancies.

Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, 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, weakness, confusion) suggestive of infection [see Warnings and Precautions (5.2)].

Atrial fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.4)] .

Hypertension: Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.5) ].

Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions (5.6)].

Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].

Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for 1 month after the last dose of IMBRUVICA [see Warnings and Precautions (5.8)].

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 (2.6)].

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.

Advise patients to maintain adequate hydration.

DOSAGE AND ADMINISTRATION

2 MCL and MZL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).

CLL/SLL and WM: 420 mg taken orally once daily (three 140 mg capsules once daily) (2.2).

Capsules should be taken orally with a glass of water.

Do not open, break, or chew the capsules (2.1).

2.1 Dosing Guidelines Administer IMBRUVICA orally once daily at approximately the same time each day.

Swallow the capsules whole with water.

Do not open, break, or chew the capsules.

2.2 Dosage Mantle Cell Lymphoma and Marginal Zone Lymphoma The recommended dose of IMBRUVICA for MCL and MZL is 560 mg (four 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s Macroglobulinemia The recommended dose of IMBRUVICA for CLL/SLL and WM is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

The recommended dose of IMBRUVICA for CLL/SLL when used in combination with bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

2.3 Dose Modifications for Adverse Reactions Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities.

Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose.

If the toxicity reoccurs, reduce dose by 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 are described below: Toxicity Occurrence MCL and MZL Dose Modification After Recovery Starting Dose = 560 mg CLL/SLL and WM Dose Modification After Recovery Starting Dose = 420 mg First Restart at 560 mg daily Restart at 420 mg daily Second Restart at 420 mg daily Restart at 280 mg daily Third Restart at 280 mg daily Restart at 140 mg daily Fourth Discontinue IMBRUVICA 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 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, fosamprenavir, crizotinib, imatinib, verapamil, and ciprofloxacin) [see Drug Interactions (7.1)].

Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of IMBRUVICA toxicity.

2.5 Dose Modifications for Use in Hepatic Impairment For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily (one capsule).

Avoid the use of IMBRUVICA in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.6 Missed Dose If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day.

Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.