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.

ZIRABEV (BLA-761099)

(BEVACIZUMAB-BVZR)

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

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02/17/2023 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Infusion-Related Reactions

(Additions and/or revisions underlined)

Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions with the first dose occurred in <3% of patients and severe reactions occurred in 0.4% of patients.

02/09/2021 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Gastrointestinal Perforations and Fistulae

(Additions and/or revisions underlined)

Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1)].

Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from <1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.

Avoid ZIRABEV in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ.

5.2 Surgery and Wound Healing Complications

(Additions and/or revisions underlined)

In a controlled clinical study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received bevacizumab and 0.7% in patients who did not receive bevacizumab [see Adverse Reactions (6.1)].

In patients who experience wound healing complications during ZIRABEV treatment, withhold ZIRABEV until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established [see Dosage and Administration (2.7)].

Necrotizing fasciitis including fatal cases, has been reported in patients receiving bevacizumab usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue ZIRABEV in patients who develop necrotizing fasciitis.

5.9 Infusion-Related Reactions

(Additions and/or revisions underlined)

Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in <3% of patients and severe reactions occurred in 0.4% of patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

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

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Gastrointestinal Perforations and Fistulae

Bevacizumab products may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [see Warnings and Precautions (5.1)].

Surgery and Wound Healing Complications

Bevacizumab products can increase the risk of wound healing complications. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions (5.2)].