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.

ZYNRELEF KIT (NDA-211988)

(BUPIVACAINE; MELOXICAM)

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

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11/21/2024 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Serious Skin Reactions

Additions and/or revisions underlined:

NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of ZYNRELEF or other products containing NSAIDs. 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.

ZYNRELEF

Injury, Poisoning, and Procedural Complications: Wound necrosis, wound dehiscence.

Surgical and Medical Procedures: Post-procedural drainage.

NSAIDs

Skin and Appendages: Exfoliative dermatitis, SJS, TEN, and FDE [see Warnings and Precautions (5.14)].

01/23/2024 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use

Newly added subsection:

The safety and effectiveness of intra-articular use of ZYNRELEF in orthopedic surgical procedures other than for foot and ankle procedures have not been established, and ZYNRELEF is not approved for use via other intra-articular administration routes. Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration [see Nonclinical Toxicology (13.2)].

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions have been associated with bupivacaine HCl or meloxicam and are discussed in greater detail in other sections of the labeling:

…

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

The safety of ZYNRELEF has been evaluated in a total of 1627 patients undergoing various surgical procedures across 14 clinical studies including 7 randomized, double-blind, bupivacaine- and placebo- controlled and saline placebo-controlled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics, of whom 1183 received ZYNRELEF by instillation. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 51 years), with 53.0% female, 82.1% White, 13.7% African-American, and 4.3% all other races.

Common Adverse Reactions

The safety of ZYNRELEF has been evaluated in 1064 patients who received ZYNRELEF in single doses up to 400 mg/12 mg via instillation into the surgical site, including 533 patients undergoing a soft tissue surgical procedure (herniorrhaphy, abdominoplasty, augmentation mammoplasty, or Cesarean section) and 531 patients undergoing an orthopedic surgical procedure (bunionectomy, total knee arthroplasty, total shoulder arthroplasty, or lumbar spinal surgery). The most common adverse reactions (incidence greater than or equal to 5% and higher than placebo) following ZYNRELEF administration among patients undergoing soft tissue procedures was vomiting and among patients undergoing orthopedic procedures were constipation and headache.

The safety of ZYNRELEF as part of a scheduled, non-opioid multimodal analgesic regimen including 1 or more other NSAIDs has been evaluated in a total of 473 patients undergoing soft tissue procedures or orthopedic procedures. NSAIDs included ibuprofen, ketorolac, and celecoxib. In these studies, the most common adverse reactions (incidence of greater than or equal to 2%) potentially associated with NSAIDs were pruritus and postoperative anemia. Rare but clinically serious NSAID-related adverse events, including peptic ulcer hemorrhage, gastritis requiring hospitalization, hematemesis and melena, gastrointestinal hemorrhage, and increased hepatic enzymes, were observed in subjects with predisposing risk factors (i.e., concomitant comorbidities and/or on concomitant medications such as anticoagulant and/or antiplatelet medications) that increased the risk for NSAID-related gastrointestinal toxicity.

Adverse Reactions Reported in Phase 3 and 2b Placebo-controlled Trials

…

6.2 Postmarketing Experience

Newly added subsection:

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

These adverse reactions involve the following 2 system organ classes: Injury, Poisoning, and Procedural Complications (wound necrosis, wound dehiscence) and Surgical and Medical Procedures (post-procedural drainage).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of patients undergoing various surgical procedures who were exposed to ZYNRELEF in clinical studies (N=1627), 288 patients (17.7%) were greater than or equal to 65 years old, while 83 (5.1%) were greater than or equal to 75 years old. No overall differences in safety or efficacy were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12/08/2021 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Chondrolysis

Additions and/or revisions underlined:

Limit exposure to articular cartilage due to the potential risk of chondrolysis.

Intra-articular infusions of local anesthetics, following arthroscopic and other surgical procedures is an unapproved use, and there have been post marketing reports of chondrolysis in patients receiving such infusions …