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-217003)

(IBRUTINIB)

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

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10/21/2025 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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

. . .

Eye disorders: uveitis

12/20/2024 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

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

…

05/09/2024 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Hepatotoxicity, Including Drug-Induced Liver Injury

New subsection added:

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including IMBRUVICA.

Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA. For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hepatotoxicity, including DILI [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis, drug-induced liver injury
…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hepatotoxicity, including drug-induced liver injury:

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during IMBRUVICA treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.7)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What are the possible side effects of IMBRUVICA?

IMBRUVICA may cause serious side effects, including:

…

Liver problems. Liver problems, which may be severe or life-threatening, or lead to death, can happen in people treated with IMBRUVICA. Your healthcare provider will do blood tests to check your liver before and during treatment with IMBRUVICA. Tell your healthcare provider or get medical help right away if you have any signs of liver problems, including stomach pain or discomfort, dark-colored urine, or yellow skin and eyes.
…
The most common side effects of IMBRUVICA in adults with B-cell malignancies (CLL/SLL and WM) include:
- low platelet count
- muscle, bone, and joint pain
- low red blood cell count (anemia)
- diarrhea
- low white blood cell count
- bruising
- tiredness
- rash
- nausea
  …
  How should I store IMBRUVICA?
  …

IMBRUVICA capsules and oral suspension come in a bottle with a child-resistant cap.
…

02/22/2024 (SUPPL-2)

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%.

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)].

5.6 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. 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

(Extensive changes; please refer to label for complete information)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

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.

Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.8 times the exposure in patients with CLL/SLL or WM 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 ? 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)].

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

PATIENT INFORMATION

(Extensive changes; please refer to label for complete information)