Ibrutinib Capsules

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.

Dosage Forms And Strengths

140 mg capsules

Storage And Handling

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 until dispensing.

Distributed and Marketed by: Pharmacyclics LLC Sunnyvale, CA USA 94085. Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044. For more information call 1-877-877-3536. Revised: Mar 2016

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.

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.

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).

Pharmacokinetics

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. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 – 3.9) and doubled when combined with a meal. Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting.

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 volume of distribution (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10000 L.

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.

Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 L/h in fasted and fed conditions, respectively. 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 (37 to 84 years) does not alter ibrutinib systemic clearance.

Gender does not alter ibrutinib systemic clearance.

Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance (CrCL) > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CrCL < 25 mL/min) or in patients on dialysis.

Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of IMBRUVICA was administered in non-cancer subjects. Ibrutinib AUC increased 2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and severe (n=8) hepatic impairment relative to subjects with normal liver function. Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations].

Drug Interactions

In a sequential design trial of 18 healthy, fasted 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 fasted conditions indicate that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 5- to 8-fold.

PK data from a dedicated drug interaction trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by more than 13- and 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib by up to 3-fold.

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.

In vitro studies indicated that ibrutinib is not a substrate of P-gp (p-glycoprotein) or BCRP (breast cancer resistance protein) transporters but is an in vitro inhibitor of P-gp and BCRP. Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1) but may inhibit BCRP. Ibrutinib may have an effect on P-gp or BCRP substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp or BCRP substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their blood concentration.

Clinical Studies

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 10.

Table 10: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL

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.

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.

Chronic Lymphocytic Leukemia

The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled trial and two randomized, controlled trials.

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.

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 11 and the Kaplan-Meier curves for PFS, assessed by independent review committee (IRC) according to IWCLL criteria, and OS are shown in Figures 1 and 2, respectively.

Table 11: Efficacy Results in Study 2

Figure 1: Kaplan-Meier Curve of Progression Free Survival (ITT Population) in Study 2

Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Study 2

Study 2 included 127 patients with del 17p CLL. 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 IRC. Efficacy results for del 17p CLL are shown in Table 12.

Table 12: Efficacy Results in Patients with del 17p CLL

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. After confirmed progression, patients on chlorambucil were able to crossover to ibrutinib.

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%).

Efficacy results for Study 3 are shown in Table 13 and the Kaplan-Meier curve for PFS, assessed by independent review committee (IRC) according to IWCLL criteria is shown in Figure 3.

Table 13: Efficacy Results in Study 3

Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Study 3

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).

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 14.

Table 14: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with WM

The median time to response was 1.2 months (range, 0.7-13.4 months).

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hemorrhage [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Cytopenias [see WARNINGS AND PRECAUTIONS]
• Atrial Fibrillation [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Second Primary Malignancies [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

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.

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

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.

The data described below reflect exposure to IMBRUVICA in one single arm, open-label clinical trial and two randomized controlled clinical trials in patients with CLL/SLL. Study 1 included 48 patients with previously treated CLL, Study 2 included 391 randomized patients with previously treated CLL or SLL who received single agent ibrutinib or ofatumumab, and Study 3 included 269 randomized patients 65 years or older with treatment na�ve CLL or SLL who received single agent ibrutinib or chlorambucil.

The most commonly occurring adverse reactions in Studies 1, 2, and 3 in patients with CLL/SLL receiving IMBRUVICA ( ≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, musculoskeletal pain, fatigue, bruising, nausea, rash, pyrexia and cough. Four to ten percent of patients receiving IMBRUVICA in Studies 1, 2, and 3 discontinued treatment due to adverse reactions. These included pneumonia, subdural hematomas and atrial fibrillation (1% each). Adverse reactions leading to dose reduction occurred in approximately 4% of patients.

Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1

Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients in Study 2

Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in Study 3.

Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients in Study 3

The data described below reflect exposure to IMBRUVICA in an open-label clinical trial that included 63 patients with previously treated WM.

The most commonly occurring adverse reactions in the WM trial ( ≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.

Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients.

Adverse reactions and laboratory abnormalities described below in Tables 8 and 9 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.

Table 8: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenstr�m's Macroglobulinemia (N=63)

Table 9: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Diarrhea

Diarrhea of any grade occurred at a rate of 47% (range, 37% to 63%) of patients treated with IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 15%) and Grade 3 in 4% (range, 0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade diarrhea was 8 days (range, 0 to 627), of Grade 2 was 28 days (range, 1 to 540) and of Grade 3 was 77 days (range, 3 to 627). Of the patients who reported diarrhea, 83% had complete resolution, 2% had partial improvement and 15% had no reported improvement at time of analysis. The median time from onset to resolution or improvement of any grade diarrhea was 5 days (range, 1 to 408), and was similar for Grades 2 and 3. Less than 1% of patients discontinued IMBRUVICA due to diarrhea.

Visual Disturbance

Blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (10% Grade 1, 1% Grade 2). The median time to first onset was 92 days (range, 1 to 414 days). Of the patients with visual disturbance, 58% had complete resolution and 42% had no reported improvement at time of analysis. The median time from onset to resolution or improvement was 29 days (range, 1 to 202 days).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. Severe liver toxicities, such as hepatic failure, have also been reported.

Read the entire FDA prescribing information for Imbruvica (Ibrutinib Capsules)