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Brand Name: Ibruxen

Originator/Innovator Brand: IMBRUVICA

Initial U.S. Approval: 2013

Dosage Form: Capsule

Composition: Each Capsule Contains Ibrutinib 140 mg INN.

-Indications

Ibruxen  is a kinase inhibitor indicated for the treatment of adult patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on the 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).
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
  • Waldenström’s macroglobulinemia (WM).
  • 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 the overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

DOSAGE AND ADMINISTRATION

Dosing Guidelines

Administer Ibrutinib (Ibruxen) orally once daily at approximately the same time each day. Swallow the capsules whole with water.

Do not open, break, or chew the capsules.

Recommended Dosage

Mantle Cell Lymphoma and Marginal Zone Lymphoma

The recommended dose of Ibrutinib (Ibruxen) 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

 Waldenstrom Macroglobulinemia (WM)

The recommended dose of Ibrutinib (Ibruxen) 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 Ibrutinib 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.

Chronic Graft versus Host Disease

The recommended dose of Ibrutinib (Ibruxen) for cGVHD is 420 mg (three 140 mg capsules) orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, Ibrutinib should be discontinued considering the medical assessment of the individual patient.

Dose Modications for Adverse Reactions

Interrupt Ibrutinib 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), Ibrutinib 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 Ibrutinib.

Toxicity occurrence

MCL dose modification after recovery

CLL/WM dose modification after recovery

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 Ibrutinib

discontinue Ibrutinib

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.

Dose Modications 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 Ibrutinib therapy until the CYP3A inhibitor is no longer needed. Reduce Ibrutinib 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). Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of Ibrutinib toxicity.

Dose Modications 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 Ibrutinib in patients with moderate or severe hepatic impairment (Child-Pugh classes Band C).

Missed Dose

If a dose of Ibrutinib 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 Ibrutinib should not be taken to make up for the missed dose.

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage, Infections, Cytopenias, Atrial Fibrillation, Hypertension, Second Primary Malignancies and Tumor Lysis Syndrome.

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. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

DRUG INTERACTIONS

Effect of CYP3A Inhibitors on Ibrutinib

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 Ibrutinib 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 Ibrutinib 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 Ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of Ibrutinib toxicity.

Avoid grape fruit and Seville oranges during Ibrutinib treatment, as these contain moderate inhibitors of CYP3A.

Effect of CYP3A Inducers on Ibrutinib

Administration of Ibrutinib with rifampin, a strong CYP3A inducer, decreased Ibrutinib Cmax and AUC by approximately 13 & 10 fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John’sWort). Consider alternative agents with less CYP3A induction.

WARNINGS AND PRECAUTIONS

  • Hemorrhage: Monitor for bleeding and manage .
  • Infections: Monitor patients for fever and infections, evaluate promptly, and treat.
  • Cytopenias: Check complete blood counts monthly.
  • Cardiac arrhythmias: Monitor for symptoms of arrhythmias and manage.
  • Hypertension: Monitor blood pressure and treat.
  • Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas.
  • Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions. Monitor and treat for TLS.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

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 in the WARNINGS AND PRECAUTIONS reflect exposure to IBRUTINIB in 6 trials as a single agent at 420 mg orally once daily in 475 patients and at 560 mg orally once daily in 174 patients and in 4 trials administered in combination with other drugs at 420 mg orally once daily in 827 patients. Among these 1,476 patients with B-cell malignancies who received IBRUTINIB, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. In this pooled safety population of 1,476 patients with B-cell malignancies, the most common adverse reactions (≥30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.

Mantle Cell Lymphoma

The data described below reflect exposure to IBRUTINIB in a clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most common 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 IBRUTINIB therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal (ULN) occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IBRUTINIB 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)

Body System

Adverse Reaction

          All Grades (%) 

Grade 3 or Higher (%)

Gastrointestinal disorders

Diarrhea

Nausea

Constipation

Abdominal pain

Vomiting

Stomatitis

Dyspepsia

51

31

25

24

23

17

11

5

0

0

5

0

1

0

General disorders and

administration site

conditions

Fatigue 

Peripheral edema 

Pyrexia 

Asthenia

41

35

18

14

5

3

1

3

Musculoskeletal and

connective tissue disorders

Musculoskeletal pain

Muscle spasms

Arthralgia 

37

14

11

     1

     0

     0

Infections and infestations

Upper respiratory tract infection

Urinary tract infection

Pneumonia

Skin infections

Sinusitis

34

14

14

14

13

0

3

8

5

1

Skin and subcutaneous

tissue disorders

Bruising

Rash

Petechiae

30

25

11

0

3

0

Respiratory, thoracic and

mediastinal disorders 

Dyspnea

Cough 

Epistaxis

27

19

11

5

0

0

Metabolism and nutrition

disorders 

Decreased appetite

Dehydration

21

12

2

4

Nervous system disorders

Dizziness

Headache

14

13

0

0

Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with MCL (N=111) 

Percent of Patients (N=111)

All Grades (%)

Grade 3 or 4 (%)

Platelets decreased 

57

17

Neutrophils decreased

47

29

Hemoglobin decreased

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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure to IBRUTINIB in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IBRUTINIB). In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IBRUTINIB or ofatumumab.RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IBRUTINIB or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IBRUTINIB in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IBRUTINIB in combination with obinutuzumab or chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IBRUTINIB in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR). The most common adverse reactions in patients with CLL/SLL receiving IBRUTINIB (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Four to 10 percent of patients with CLL/SLL receiving IBRUTINIB discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 9% of patients.

Study 1102

Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent IBRUTINIB 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months.

RESONATE

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.

RESONATE-2

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2. 

iLLUMINATE

Adverse reactions described below in Table 10 reflect exposure to IBRUTINIB + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.

E1912

Adverse reactions described below in Table 11 reflect exposure to IBRUTINIB + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.

Waldenström’s Macroglobulinemia and Marginal Zone Lymphoma

The data described below reflect exposure to IBRUTINIB in three single-arm open-label clinical trials (Study 1118, Study 1121, and INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM or MZL, including a total n=307 patients overall and n=232 patients exposed to IBRUTINIB. Study 1118 included 63 patients with previously treated WM who received single agent IBRUTINIB. Study 1121 included 63 patients with previously treated MZL who received single agent IBRUTINIB. INNOVATE included 150 patients with treatment naïve or previously treated WM who received IBRUTINIB or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received IBRUTINIB. The most common adverse reactions in Studies 1118, 1121, and INNOVATE (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia,rash, fatigue, and nausea. Seven percent of patients receiving IBRUTINIB across Studies 1118, 1121, and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 13% of patients. Study 1118 and INNOVATE Monotherapy Arm Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.

INNOVATE

Adverse reactions described below in Table 15 reflect exposure to IBRUTINIB + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE. Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR. 

Study 1121

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 11.6 months in Study 1121.

Chronic Graft versus Host Disease

The data described below reflect exposure to IBRUTINIB in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy.

The most common adverse reactions in the cGVHD trial (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3. Twenty-four percent of patients receiving IBRUTINIB in the cGVHD trial discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients. Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect exposure to IBRUTINIB with a median duration of 4.4 months in the cGVHD trial.

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), the incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias,ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IBRUTINIB compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with IBRUTINIB compared to patients in the control arm.

Diarrhea

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), diarrhea of any grade occurred at a rate of 43% of patients treated with IBRUTINIB compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IBRUTINIB -treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IBRUTINIB due to diarrhea compared with 0% in the control arm. Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IBRUTINIB -treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus 89% had complete resolution, and 15% versus 11% had not reported resolution at time of analysis in IBRUTINIB -treated patients compared to the control arm, respectively. The median time from onset to resolution in IBRUTINIB -treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range, 1 to 56) for Grade 3 diarrhea in IBRUTINIB -treated subjects compared to the control arm, respectively.

Visual Disturbance

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IBRUTINIB (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and <1% Grade 2 and 3). Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IBRUTINIB -treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had complete resolution and 40% versus 29% had not reported resolution at the time of analysis in IBRUTINIB -treated patients compared to the control arm, respectively. The median time from onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IBRUTINIB -treated subjects compared to the control arm, respectively.

Long-Term Safety

The safety data from long-term follow-up over 5 years of 1,178 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated with IBRUTINIB were analyzed. The median treatment duration for CLL/SLL was 51 months (range, 0.2 to 98 months). The median treatment duration for MCL was 11 months (range, 0 to 87 months). The cumulative rate of hypertension increased over time with prolonged IBRUTINIB treatment. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.

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Ibruxen


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Description of product

Brand Name: Ibruxen

Originator/Innovator Brand: IMBRUVICA

Initial U.S. Approval: 2013

Dosage Form: Capsule

Composition: Each Capsule Contains Ibrutinib 140 mg INN.

-Indications

Ibruxen  is a kinase inhibitor indicated for the treatment of adult patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on the 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).
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
  • Waldenström’s macroglobulinemia (WM).
  • 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 the overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

DOSAGE AND ADMINISTRATION

Dosing Guidelines

Administer Ibrutinib (Ibruxen) orally once daily at approximately the same time each day. Swallow the capsules whole with water.

Do not open, break, or chew the capsules.

Recommended Dosage

Mantle Cell Lymphoma and Marginal Zone Lymphoma

The recommended dose of Ibrutinib (Ibruxen) 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

 Waldenstrom Macroglobulinemia (WM)

The recommended dose of Ibrutinib (Ibruxen) 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 Ibrutinib 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.

Chronic Graft versus Host Disease

The recommended dose of Ibrutinib (Ibruxen) for cGVHD is 420 mg (three 140 mg capsules) orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, Ibrutinib should be discontinued considering the medical assessment of the individual patient.

Dose Modications for Adverse Reactions

Interrupt Ibrutinib 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), Ibrutinib 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 Ibrutinib.

Toxicity occurrence

MCL dose modification after recovery

CLL/WM dose modification after recovery

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 Ibrutinib

discontinue Ibrutinib

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.

Dose Modications 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 Ibrutinib therapy until the CYP3A inhibitor is no longer needed. Reduce Ibrutinib 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). Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of Ibrutinib toxicity.

Dose Modications 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 Ibrutinib in patients with moderate or severe hepatic impairment (Child-Pugh classes Band C).

Missed Dose

If a dose of Ibrutinib 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 Ibrutinib should not be taken to make up for the missed dose.

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage, Infections, Cytopenias, Atrial Fibrillation, Hypertension, Second Primary Malignancies and Tumor Lysis Syndrome.

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. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

DRUG INTERACTIONS

Effect of CYP3A Inhibitors on Ibrutinib

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 Ibrutinib 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 Ibrutinib 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 Ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of Ibrutinib toxicity.

Avoid grape fruit and Seville oranges during Ibrutinib treatment, as these contain moderate inhibitors of CYP3A.

Effect of CYP3A Inducers on Ibrutinib

Administration of Ibrutinib with rifampin, a strong CYP3A inducer, decreased Ibrutinib Cmax and AUC by approximately 13 & 10 fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John’sWort). Consider alternative agents with less CYP3A induction.

WARNINGS AND PRECAUTIONS

  • Hemorrhage: Monitor for bleeding and manage .
  • Infections: Monitor patients for fever and infections, evaluate promptly, and treat.
  • Cytopenias: Check complete blood counts monthly.
  • Cardiac arrhythmias: Monitor for symptoms of arrhythmias and manage.
  • Hypertension: Monitor blood pressure and treat.
  • Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas.
  • Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions. Monitor and treat for TLS.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

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 in the WARNINGS AND PRECAUTIONS reflect exposure to IBRUTINIB in 6 trials as a single agent at 420 mg orally once daily in 475 patients and at 560 mg orally once daily in 174 patients and in 4 trials administered in combination with other drugs at 420 mg orally once daily in 827 patients. Among these 1,476 patients with B-cell malignancies who received IBRUTINIB, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. In this pooled safety population of 1,476 patients with B-cell malignancies, the most common adverse reactions (≥30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.

Mantle Cell Lymphoma

The data described below reflect exposure to IBRUTINIB in a clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most common 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 IBRUTINIB therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal (ULN) occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IBRUTINIB 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)

Body System

Adverse Reaction

          All Grades (%) 

Grade 3 or Higher (%)

Gastrointestinal disorders

Diarrhea

Nausea

Constipation

Abdominal pain

Vomiting

Stomatitis

Dyspepsia

51

31

25

24

23

17

11

5

0

0

5

0

1

0

General disorders and

administration site

conditions

Fatigue 

Peripheral edema 

Pyrexia 

Asthenia

41

35

18

14

5

3

1

3

Musculoskeletal and

connective tissue disorders

Musculoskeletal pain

Muscle spasms

Arthralgia 

37

14

11

     1

     0

     0

Infections and infestations

Upper respiratory tract infection

Urinary tract infection

Pneumonia

Skin infections

Sinusitis

34

14

14

14

13

0

3

8

5

1

Skin and subcutaneous

tissue disorders

Bruising

Rash

Petechiae

30

25

11

0

3

0

Respiratory, thoracic and

mediastinal disorders 

Dyspnea

Cough 

Epistaxis

27

19

11

5

0

0

Metabolism and nutrition

disorders 

Decreased appetite

Dehydration

21

12

2

4

Nervous system disorders

Dizziness

Headache

14

13

0

0

Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with MCL (N=111) 

Percent of Patients (N=111)

All Grades (%)

Grade 3 or 4 (%)

Platelets decreased 

57

17

Neutrophils decreased

47

29

Hemoglobin decreased

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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure to IBRUTINIB in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IBRUTINIB). In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IBRUTINIB or ofatumumab.RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IBRUTINIB or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IBRUTINIB in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IBRUTINIB in combination with obinutuzumab or chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IBRUTINIB in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR). The most common adverse reactions in patients with CLL/SLL receiving IBRUTINIB (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Four to 10 percent of patients with CLL/SLL receiving IBRUTINIB discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 9% of patients.

Study 1102

Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent IBRUTINIB 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months.

RESONATE

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.

RESONATE-2

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2. 

iLLUMINATE

Adverse reactions described below in Table 10 reflect exposure to IBRUTINIB + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.

E1912

Adverse reactions described below in Table 11 reflect exposure to IBRUTINIB + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.

Waldenström’s Macroglobulinemia and Marginal Zone Lymphoma

The data described below reflect exposure to IBRUTINIB in three single-arm open-label clinical trials (Study 1118, Study 1121, and INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM or MZL, including a total n=307 patients overall and n=232 patients exposed to IBRUTINIB. Study 1118 included 63 patients with previously treated WM who received single agent IBRUTINIB. Study 1121 included 63 patients with previously treated MZL who received single agent IBRUTINIB. INNOVATE included 150 patients with treatment naïve or previously treated WM who received IBRUTINIB or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received IBRUTINIB. The most common adverse reactions in Studies 1118, 1121, and INNOVATE (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia,rash, fatigue, and nausea. Seven percent of patients receiving IBRUTINIB across Studies 1118, 1121, and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 13% of patients. Study 1118 and INNOVATE Monotherapy Arm Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.

INNOVATE

Adverse reactions described below in Table 15 reflect exposure to IBRUTINIB + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE. Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR. 

Study 1121

Adverse reactions and laboratory abnormalities reflect exposure to IBRUTINIB with a median duration of 11.6 months in Study 1121.

Chronic Graft versus Host Disease

The data described below reflect exposure to IBRUTINIB in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy.

The most common adverse reactions in the cGVHD trial (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3. Twenty-four percent of patients receiving IBRUTINIB in the cGVHD trial discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients. Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect exposure to IBRUTINIB with a median duration of 4.4 months in the cGVHD trial.

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), the incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias,ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IBRUTINIB compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with IBRUTINIB compared to patients in the control arm.

Diarrhea

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), diarrhea of any grade occurred at a rate of 43% of patients treated with IBRUTINIB compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IBRUTINIB -treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IBRUTINIB due to diarrhea compared with 0% in the control arm. Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IBRUTINIB -treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus 89% had complete resolution, and 15% versus 11% had not reported resolution at time of analysis in IBRUTINIB -treated patients compared to the control arm, respectively. The median time from onset to resolution in IBRUTINIB -treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range, 1 to 56) for Grade 3 diarrhea in IBRUTINIB -treated subjects compared to the control arm, respectively.

Visual Disturbance

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IBRUTINIB and 5.3 months for 958 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IBRUTINIB (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and <1% Grade 2 and 3). Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IBRUTINIB -treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had complete resolution and 40% versus 29% had not reported resolution at the time of analysis in IBRUTINIB -treated patients compared to the control arm, respectively. The median time from onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IBRUTINIB -treated subjects compared to the control arm, respectively.

Long-Term Safety

The safety data from long-term follow-up over 5 years of 1,178 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated with IBRUTINIB were analyzed. The median treatment duration for CLL/SLL was 51 months (range, 0.2 to 98 months). The median treatment duration for MCL was 11 months (range, 0 to 87 months). The cumulative rate of hypertension increased over time with prolonged IBRUTINIB treatment. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.

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