Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

IMBRUVICA (NDA-205552)

(IBRUTINIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/18/2023 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Infections

(Additions and/or revisions underlined)

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B- cell malignancies who received IMBRUVICA in clinical trials [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. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.

5.4 Hypertension

(Additions and/or revisions underlined)

Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see Adverse Reactions (6.1)]. Based on data from a subset of these patients (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98 months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%.

5.6 Second Primary Malignancies

(Additions and/or revisions underlined)

Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

5.8 Embryo-Fetal Toxicity

(Additions and/or revisions underlined

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 embryo-fetal toxicity including malformations at exposures that were 3-20 times higher than those reported in patients with hematologic malignancies.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely variable conditions, adverse reaction 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.

Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. The most common adverse reactions (greater than or equal to 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens.

…

Waldenström’s Macroglobulinemia

The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials (Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA.

INNOVATE included 150 patients with treatment naïve or previously treated WM who received IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who received IMBRUVICA after failure of prior rituximab-containing therapy.

The most common adverse reactions in Studies 1118 and INNOVATE (greater than or equal to 20%) were neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and nausea.

Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reaction leading to discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in 14% of patients.

…

Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis. Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis and acute respiratory distress syndrome (ARDS).

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

(Additions and/or revisions underlined)

IMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.

…

The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62% were greater than or equal to 65 years of age, while 22% were greater than or equal to 75 years of age [see Clinical Studies (14.1, 14.2, 14.3)]. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA [see Adverse Reactions (6.1)].

08/24/2022 (SUPPL-36)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Chronic Graft versus Host Disease

…

iMAGINE

The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m2 orally once daily [see Clinical Studies (14.5)]. The median duration of exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).

Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of patients. Adverse reactions which resulted in permanent discontinuation in at least two patients included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dose reduction in at least two patients included stomatitis.

The most common (greater than or equal to 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

Table 24 summarizes the adverse reactions in iMAGINE.

Please refer to label to view Table 24

Table 25 summarizes the laboratory abnormalities in iMAGINE.

Please refer to label to view Table 25

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined

Of the 1,124 patients in clinical studies of IMBRUVICA for MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, MZL, and cGVHD, 64% were greater than or equal to 65 years of age, while 23% were greater than or equal to75 years of age [see Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5)]. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA [see Adverse Reactions (6.1)].

8.6 Hepatic Impairment

Additions and/or revisions underlined

Adult Patients with B-cell Malignancies

…

Patients with cGVHD

Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non- hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Dosage and Administration (2.4)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

For IMBRUVICA oral suspension, instruct patients or caregivers to read and follow the Instructions for Use for proper preparation, administration, storage and disposal [see Dosage and Administration (2.1)].

…

PATIENT INFORMATION

Additions and/or revisions underlined

What is IMBRUVICA?

IMBRUVICA is a prescription medicine used to treat:

Adults with…

Adults and children 1 year of age and older with chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy.
…
How should I take IMBRUVICA?

Take IMBRUVICA exactly as your healthcare provider tells you to take it.
Take IMBRUVICA 1 time a day at about the same time each day.
IMBRUVICA comes as capsules, tablets, and oral suspension.
If your healthcare provider prescribes IMBRUVICA capsules or tablets:
- Swallow IMBRUVICA capsules or tablets whole with a glass of water.
- Do not open, break, or chew IMBRUVICA capsules.
- Do not cut, crush, or chew IMBRUVICA tablets.
If your healthcare provider prescribes IMBRUVICA oral suspension:
- See the detailed Instructions for Use that comes with IMBRUVICA oral suspension for information about the correct way to give a dose to your child. If you have questions about how to give IMBRUVICA oral suspension, talk to your healthcare provider.
- Do not use if the carton seal is broken or missing.
  …
  The most common side effects of IMBRUVICA in adults or children 1 year of age and older with cGVHD include:

tiredness o muscle and joint pain o nausea
low red blood cell count (anemia) o fever o stomach pain
bruising o muscle spasms o pneumonia
diarrhea o mouth sores (stomatitis) o headache
low platelet count o bleeding
…
How should I store IMBRUVICA?

Store IMBRUVICA capsules and tablets at room temperature between 68°F and 77°F (20°C and 25°C).
Keep IMBRUVICA capsules in the original container with the lid tightly closed.
Keep IMBRUVICA tablets in the original carton.
Store IMBRUVICA oral suspension bottle between 36°F and 77°F (2°C and 25°C). Do not freeze.
Use IMBRUVICA oral suspension within 60 days after first opening the bottle. Throw away (discard) any unused portion 60 days after opening.
…

08/24/2022 (SUPPL-38)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

Chronic GVHD

The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older.

Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which included pediatric patients age 1 year and older with previously treated cGVHD, including patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2 years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age.

Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].

The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based on body-surface area (BSA) [see Dosage and Administration (2.1)].

The safety and effectiveness of IMBRUVICA have not been established for this indication in pediatric patients less than 1 year of age.

Mature B-cell Non-Hodgkin Lymphoma

The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were assessed but have not been established based on an open-label, randomized study (NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years, with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for futility. In the randomized population, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.

MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, MZL

The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, or MZL.

05/11/2022 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Cardiac Arrhythmias, Cardiac Failure, and Sudden Death

Subsection title revised

Additions and/or revisions underlined:

Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens.

These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections [see Adverse Reactions (6.1)].

Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines [see Dosage and Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.

5.4 Hypertension

Additions and/or revisions underlined:

Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see Adverse Reactions (6.1)]. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration (2.2)].

5.5 Cytopenias

Additions and/or revisions underlined:

In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].

5.6 Second Primary Malignancies

Addition and/or revisions underlined:

Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer (6%)

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

…

Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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

Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Newly added information:

IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Cardiac arrhythmias, cardiac failure, and sudden death:

Inform patients of the possibility of irregular heart rhythm, heart failure and sudden death.

…

Other Important Information:

Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the oral dosage (capsules or tablets) should be swallowed…

PATIENT INFORMATION

Additions and/or revisions underlined:

IMBRUVICA may cause serious side effects, including:

…

• Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure and death have happened in people treated with IMBRUVICA, especially in people who have an infection, an increased risk for heart disease, or have had heart rhythm problems in the past. Your heart function will be checked before and during treatment with IMBRUVICA. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles or legs, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change your IMBRUVICA dose.

…

12/22/2020 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

(Additions and/or revisions underlined)

Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA, respectively.

5.4 Cardiac Arrhythmias and Cardiac Failure

(Section title revised)

(Additions and/or revisions underlined)

Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4%, and Grade 3 or greater cardiac failure occurred in 1% of 1,476 patients who received IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias [see Adverse Reactions (6.1)].

At baseline and then periodically, monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias and cardiac failure appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and Administration (2.2)].

6 Adverse Reactions

(Additions and/or revisions underlined)

Cardiac Arrhythmias and Cardiac Failure [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

In addition, the incidence of cardiac failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm.

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA 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 IMBRUVICA compared to 19% of patients in the control arm.

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA 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 IMBRUVICA (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).

Long-Term Safety

The safety data from long-term treatment with IMBRUVICA over 5 years of 1,284 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) were analyzed. The median treatment duration was 51 months (range, 0.2 to 98 months) for CLL/SLL, 11 months (range, 0 to 87 months) for MCL, and 47 months (range, 0.3 to 61 months) for WM. The cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Additions and/or revisions underlined)

Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure and death have happened in people treated with IMBRUVICA, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past.

Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles or legs, chest discomfort, or you faint.

12/18/2020 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Long-Term Safety

08/07/2020 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42), additions and/or revisions underlined:

Additional Important Adverse Reactions

Cardiovascular Events

Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 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 IMBRUVICA compared to patients in the control arm.

The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke, cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses

04/21/2020 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Hemorrhage

… Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage.

5.2 Infections

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1, 6.2)] …

5.3 Cytopenias

5.4 Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,476 patients who received IMBRUVICA in clinical trials …

5.5 Hypertension

Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months) …

5.6 Second Primary Malignancies

Other malignancies (10%), including non-skin carcinomas (4%), occurred among the 1,476 patients who received IMBRUVICA in clinical trials …

5.8 Embryo-Fetal Toxicity

… Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose. [see Use in Specific Populations (8.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information underlined:

The data in the WARNINGS AND PRECAUTIONS reflect exposure to IMBRUVICA 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 IMBUVICA, 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 (greater than or equal to 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising.

Following Table 2 additions and/or revisions underlined:

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure to IMBRUVICA 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 IMBRUVICA). In general, patients with creatinine clearance (CLcr) less than or equal to 30 mL/min, AST or ALT greater than or equal to 2.5 x ULN, or total bilirubin greater than or equal to 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 IMBRUVICA or ofatumumab.

RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA 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 IMBRUVICA 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 IMBRUVICA in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR).

The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (greater than or equal to 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA 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 IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of greater than or equal to 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.

Following Table 10, additions and/or revisions underlined:

E1912

Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + 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.

Addition of the following Tables (please refer to label for complete information):

Table 11: Adverse Reactions Reported in at Least 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912

Table 12: Select Laboratory Abnormalities (greater than or equal to 15% Any Grade), New or Worsening from Baseline in Patients Receiving IMBRUVICA (E1912)

Following Table 19 (previously Table 17), additions and/or revisions underlined:

Diarrhea

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA 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 IMBRUVICA compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IMBRUVICA 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 …

Visual Disturbance

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA 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 IMBRUVICA (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 …

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

… the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.

All pregnancies have a background risk of birth defect

8.2 Lactation

Risk Summary

There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.

Contraception

Females

IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month following the last dose.

8.6 Hepatic Impairment

The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria.

Reduce the recommended dose when administering IMBRUVICA to patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for adverse reactions of IMBRUVICA.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-fetal toxicity:

Advise women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Lactation:

Advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the last dose [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Newly added section; please refer to label for complete information.

11/21/2019 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

(Additions and/or revisions underlined)

RESONATE-2

Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 17.4 months.

(Information in tables 7 and 8 added/updated; please see label for complete information)

(New subsection added)

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 IMBRUVICA 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 IMBRUVICA 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%.

07/15/2019 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

(additions and revisions underlined)

Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (greater than or equal to Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms 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.

01/25/2019 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

(Additions and/or revisions are underlined)

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 3% of patients, with fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

…

5.2 Infections

(Additions and/or revisions are underlined)

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials …

5.4 Cardiac Arrhythmias

(Additions and/or revisions are underlined)

5.5 Hypertension

(Additions and/or revisions are underlined)

Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti- hypertensive medication throughout treatment with IMBRUVICA as appropriate.

5.6 Second Primary Malignancies

(Additions and/or revisions are underlined)

Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

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

Hemorrhage
…

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined, tables in the section have been revised; please refer to label)

…

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure in one single-arm, open-label clinical trial

(Study 1102) and four randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS, and iLLUMINATE) in patients with CLL/SLL (n=1,506 total and n=781 patients exposed to IMBRUVICA). Patients with creatinine clearance (CrCl) less than or equal to ? 30 mL/min, AST or ALT greater than or equal to 2.5 x ULN (upper limit of normal), or total bilirubin greater than or equal to greater than or equal to 1.5x ULN (unless of non-hepatic origin) were excluded from these trials. 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 IMBRUVICA or ofatumumab, RESONATE-2 included 267 randomized patients with treatment naïve-CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil, HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab, and iLLUMINATE included 228 randomized patients with treatment naïve CLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab.

The most commonly occurring adverse reactions in patients with CLL/SLL receiving IMBRUVICA (greater than or equal to 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, bruising, nausea, fatigue, pyrexia, hemorrhage, and cough.

Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia. Adverse reactions leading to dose reduction occurred in approximately 7% of patients.

Study 1102

Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of greter than or equal to 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.

….

iLLUMINATE

Adverse reactions described below in Table 9 reflect exposure to IMBRUVICA + 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.

…

Study 1118 and INNOVATE Monotherapy Arm

Adverse reactions and laboratory abnormalities described below in Tables 10 and 11 reflect exposure to IMBRUVICA 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 12 reflect exposure to IMBRUVICA + 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.

…

Study 1121

Adverse reactions and laboratory abnormalities described below in Tables 13 and 14 reflect exposure to IMBRUVICA with a median duration of 11.6 months in Study 1121.

…

Adverse reactions and laboratory abnormalities described below in Tables 15 and 16 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial.

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 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 0.5% and of Grade 3 or greater was 0.2% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 9% versus 1.4% and for Grade 3 or greater was 4.1% versus 0.4% in patients treated with IMBRUVICA compared to patients in the control arm.

Diarrhea

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm), diarrhea of any grade occurred at a rate of 39% of patients treated with IMBRUVICA compared to 18% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. 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 IMBRUVICA-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 IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution in IMBRUVICA-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 IMBRUVICA-treated subjects compared to the control arm, respectively. Less than 1% of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.

Visual Disturbance

In randomized controlled trials (n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (10% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (6% Grade 1 and <1% Grade 2 and 3). The median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-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 IMBRUVICA-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 IMBRUVICA-treated subjects compared to the control arm, respectively.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis
Infections: hepatitis B reactivation
Nervous system disorders: peripheral neuropathy

8 Use in Specific Populations

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

…

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential prior to initiating IMBRUVICA therapy.

…

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were ? 65 years of age, while 23% were ?75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA.

Other

PATIENT INFORMATION

(Newly added subsection, please refer to the label)

08/24/2018 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

(Additions and/or revisions are underlined)

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 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA…

5.2 Infections

(Additions and/or revisions are underlined)

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials…

5.3 Cytopenias

(Additions and/or revisions are underlined)

Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA…

5.4 Cardiac Arrhythmias

(Additions and/or revisions are underlined)

Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias…

5.5 Hypertension

(Additions and/or revisions are underlined)

Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months)…

5.6 Second Primary Malignancies

(Additions and/or revisions are underlined)

Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%)…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Pediatric studies have not been completed.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the 1011 patients in clinical studies of IMBRUVICA, 62% were greater than or equal to 65 years of age, while 22% were greater than or equal to 75 years of age…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets approximately the same time each day.
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 doses to make up the missed dose.

08/24/2018 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

(Additions and/or revisions are underlined)

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 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA…

5.2 Infections

(Additions and/or revisions are underlined)

5.3 Cytopenias

(Additions and/or revisions are underlined)

5.4 Cardiac Arrhythmias

(Additions and/or revisions are underlined)

5.5 Hypertension

(Additions and/or revisions are underlined)

Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months)…

5.6 Second Primary Malignancies

(Additions and/or revisions are underlined)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis

8 Use in Specific Populations

8.5 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Pediatric studies have not been completed.

8.6 Geriatric Use

(Additions and/or revisions are underlined)

Of the 1011 patients in clinical studies of IMBRUVICA, 62% were ? 65 years of age, while 22% were greater than or equal to 75 years of age…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets approximately the same time each day.

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 doses to make up the missed dose.

12/20/2017 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Cardiac Arrhythmias

(additions underlined)

Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

6 Adverse Reactions

(additions underlined)

…

Cardiac Arrhythmias

…

6.1 Clinical Trials Experience

(additions underlined)

…

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=1227; median treatment duration of 13.1 months for patients treated with IMBRUVICA and 9.0 months for 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 0.2%

and of Grade 3 or greater was 0.2% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 7% versus 1.5% and for Grade 3 or greater was 2.8% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm.

…

7 Drug Interactions

7.1 Effect of CYP3A Inhibitors on Ibrutinib

(additions underlined)

…

Dose modifications of IMBRUVICA are recommended when used concomitantly with posaconazole, voriconazole and moderate CYP3A inhibitors.

Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these inhibitors will be used short-term (such as anti-infectives for seven days or less).

…

8 Use in Specific Populations

8.6 Hepatic Impairment

(additions underlined)

Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria.

Dose modifications of IMBRUVICA are recommended in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients for adverse reactions of IMBRUVICA closely.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

...

Cardiac Arrhythmias:

Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort

…

08/02/2017 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Infections

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.

5.3 Cytopenias

… thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

6 Adverse Reactions

6.1 Clinical Trials Experience

Mantle Cell Lymphoma

Additions and/or revisions underlined:

The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that …

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

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure in one single-arm, open-label clinical trial

(Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to IMBRUVICA). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil, and HELIOS included 578 randomized patients …

The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and HELIOS in patients with CLL/SLL receiving IMBRUVICA (? 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1102, RESONATE, RESONATE-2, and HELIOS discontinued treatment …

Study 1102 replaces Study 1

Table 3: Non-Hemtologic Adverse Reactions in greater than or equal to 10% of Patients with CLL/SLL in Study 1102

Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102

RESONATE replaces Study 2 in subheading and in table 5 title

Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE

RESONATE-2 replaces Study 3 in subheading and in table 7 title.

HELIOS replaces Study 4 in subheading and in table 8 title

Waldenström’s Macroglobulinemia and Marginal Zone Lymphoma

Study 1118 replaces study 5 and Study 1121 replaces Study 6 throughout this section

Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 (N=63)

Table 12: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63)

Addition of the following:

Chronic Graft versus Host Disease

The data described below reflect exposure to IMBRUVICA 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 commonly occurring adverse reactions in the cGVHD trial (greater than or equal to 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 IMBRUVICA 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 Tables 13 and 14 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial.

Addition of Table 13: Non-Hematologic Adverse Reactions in Greater Than or Equal to 10% of Patients with cGVHD (N=42) and Table 14: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42) ; please see label for complete information.

6.2 Postmarketing Experience

Addition of the following:

Infections: hepatitis B reactivation

7 Drug Interactions

7.1 Effect of CYP3A Inhibitors on Ibrutinib

Additions and/or revisions underlined:

The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity.

Examplesa of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin.

Examplesa of moderate CYP3A inhibitors include: aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil.

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A.

Patients with B-cell Malignancies

Posaconazole: Reduce IMBRUVICA dose to 140 mg once daily during coadministration with posaconazole at doses of no more than 200 mg BID. Avoid the coadministration of IMBRUVICA with posaconazole at doses of greater than 200 mg BID.

Voriconazole: Reduce IMBRUVICA dose to 140 mg once daily during coadministration with any dose of voriconazole

Other Strong Inhibitors: Avoid concomitant administration of IMBRUVICA with other strong CYP3A inhibitors. Alternatively, interrupt IMBRUVICA therapy during the duration of strong CYP3A inhibitors if the inhibitor will be used short-term (such as anti-infectives for seven days or less).

Moderate Inhibitors: Reduce IMBRUVICA dose to 140 mg once daily during coadministration with any moderate CYP3A inhibitor.

Monitor patients taking concomitant strong or moderate CYP3A inhibitors more frequently for adverse reactions of IMBRUVICA.

Patients with Chronic Graft versus Host Disease

Moderate CYP3A Inhibitor

Modify the dose based on adverse reactions [see Dosage and Administration (2.3)] for patients coadministered IMBRUVICA with any moderate CYP3A inhibitor.

Strong CYP3A Inhibitors

Reduce IMBRUVICA dose to 280 mg once daily for patients coadministered IMBRUVICA with

posaconazole immediate-release tablet 200 mg BID or
posaconazole delayed-release tablet 300 mg QD or
voriconazole any dose
Modify the dose based on adverse reactions.
Avoid concomitant administration of IMBRUVICA with posaconazole at higher doses and other strong CYP3A inhibitors. If these CYP3A inhibitors will be used short-term (such as anti- infectives for seven days or less), interrupt IMBRUVICA therapy during the duration of the inhibitor.

7.2 Effect of CYP3A Inducers on Ibrutinib

Additions and/or revisions underlined:

The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers.

Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wortb.

a These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this category. The healthcare provider should consult appropriate references for comprehensive information.

b The induction potency of St. John’s wort may vary widely based on preparation.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant … embryofetal toxicity including structural abnormalities …

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk …

Animal Data

… The dose of 80 mg/kg/day in rats is approximately 14 times the exposure (AUC) in patients with MCL or MZL and 20 times …

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Avoid use of IMBRUVICA in patients with moderate or severe hepatic impairment (Child-Pugh class B and C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria.

Monitor patients for adverse reactions of IMBRUVICA and follow dose modification guidance as needed.

06/28/2016 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

Respiratory disorders: interstitial lung disease (includes multiple terms).

05/06/2016 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

Addition of:

Hepatobiliary disorders: hepatic failure (includes multiple terms)
Metabolic and nutrition disorders: tumor lysis syndrome
Skin and subcutaneous tissue disorders: anaphylactic shock, angioedema, urticarial