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.

BRUKINSA (NDA-213217)

(ZANUBRUTINIB)

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

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06/04/2024 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hepatotoxicity, Including Drug-Induced Liver Injury

Newly added subsection:

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 BRUKINSA.

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

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hepatotoxicity, including DILI [see Warnings and Precautions (5.6)]

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during postapproval use of BRUKINSA. 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.

Hepatobiliary disorder: drug-induced liver injury

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

PATIENT COUNSELING INFORMATION

Newly added information:

Hepatotoxicity, Including Drug-Induced Liver Injury:

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during BRUKINSA treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].

PATIENT INFORMATION

Additions and/or revisions underlined:

BRUKINSA 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 BRUKINSA. Your healthcare provider will do blood tests to check your liver before and during treatment with BRUKINSA. 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.

01/19/2023 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

Additions and revisions underlined:

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and

gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients.

Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

5.2 Infections

Additions and revisions underlined:

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

5.3 Cytopenias

Additions and revisions underlined:

Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%), and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

5.4 Second Primary Malignancies

Additions and revisions underlined:

Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non- melanoma skin cancer, reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

5.5 Cardiac Arrhythmias

Additions and revisions underlined:

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately [see Dosage and Administration (2.4)], and consider the risks and benefits of continued BRUKINSA treatment.

7 Drug Interactions

7.1 Effect of Other Drugs on BRUKINSA

Extensive changes to table; please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Of the 1550 patients with MCL, MZL, WM, and CLL/SLL in clinical studies with BRUKINSA, 61% were ?65 years of age, and 22% were ?75 years of age. Patients <65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (63% and 47%, respectively) than patients <65 years of age (57% and 36%, respectively). No overall differences in effectiveness were observed between younger and older patients.

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

PATIENT INFORMATION

Additions and revisions underlined:

What is BRUKINSA?

BRUKINSA is a prescription medicine used to treat adults with:

Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.
Waldenström’s macroglobulinemia (WM).
Marginal zone lymphoma (MZL) when the disease has come back or did not respond to treatment and who have received at least one certain type of treatment.
Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

. . .

BRUKINSA may cause serious side effects, including:

Bleeding problems (hemorrhage). Bleeding problems are common with BRUKINSA, and can be serious and may lead to death.

. . .

Heart rhythm problems (atrial fibrillation, atrial flutter, and ventricular arrhythmias) that can be serious and may lead to death.

09/01/2021 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hemorrhage

Additions and/or revisions underlined

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax have been reported in 3.0% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)].

…

5.2 Infections

Additions and/or revisions underlined

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 28% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred [see Adverse Reactions (6.1)].

…

5.3 Cytopenias

Additions and/or revisions underlined

Grade 3 or 4 cytopenias, including neutropenia (28%), thrombocytopenia (11%), and anemia (7%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 4% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed.

5.4 Second Primary Malignancies

Additions and/or revisions underlined

Second primary malignancies have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (4%), melanoma (1.4%), and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

5.5 Cardiac Arrhythmias

Additions and/or revisions underlined

Atrial fibrillation and atrial flutter were reported in 2.8% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events of atrial fibrillation and atrial flutter were reported in 0.8% of patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate [see Dosage and Administration (2.4)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and revisions; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined

Of the 779 patients in clinical studies with BRUKINSA, 52% were greater than or equal to 65 years of age, while 20% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between younger and older patients.

8.6 Renal Impairment

Additions and /or revisions underlined

No dosage modification is recommended in patients with mild, moderate, or severe renal impairment (CLcr ? 15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients on dialysis [see Clinical Pharmacology (12.3)].

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with BRUKINSA, including skin cancer. Advise patients to use sun protection and have monitoring for development of other cancers [see Warnings and Precautions (5.4)].

…

PATIENT INFORMATION

Additions underlined

What is BRUKINSA?

BRUKINSA is a prescription medicine used to treat adults with:

Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer
Waldenström’s macroglobulinemia (WM)
…
The most common side effects of BRUKINSA include:

decreased white blood cells
muscle or bone pain
upper respiratory tract infection
decreased red blood cells (anemia)
decreased platelet count
bruising
rash
diarrhea
bleeding
pneumonia
cough
…