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.

DEFINITY (NDA-021064)

(PERFLUTREN)

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

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03/01/2024 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypersensitivity Reactions

Additions and/or revisions underlined:

… DEFINITY is contraindicated in patients with known or suspected hypersensitivity to perflutren lipid microsphere or its components such as PEG [see Contraindications (4)].

…

5.4 Ventricular Arrhythmia Related to High Mechanical Index

Additions and/or revisions underlined:

…

The maximum recommended mechanical index for use with DEFINITY is 0.8 in adult patients and 0.3 in pediatric patients[see Dosage and Administration (2.4)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Adverse Reactions in Adults

…

Adverse reactions that led to discontinuation in a total of 15 (0.9%) subjects receiving DEFINITY in the clinical trials included urticaria, pruritus, dizziness, chest pain, dyspnea, and back pain.

Table 1 summarizes the most common adverse reactions occurring at greater than or equal to 0.5%.

Please refer to label to view Table 1.

…

Adverse Reactions in Pediatric Patients

In a study of DEFINITY in 40 pediatric patients 1 month of age and older, no new safety signals were observed [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2)].

In published studies of DEFINITY in 149 patients 5 years to 24 years of age (mean age 16.8 years; 56% male) clinically indicated for echocardiography, no additional safety signals were observed.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of DEFINITY have been established for use in pediatric patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve delineation of the left endocardial border. Use of DEFINITY for this indication is supported by evidence from adequate and well-controlled studies in adults [see Clinical Studies (14 )], a pharmacodynamic and safety study in 40 pediatric patients 1 month of age and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)], and published studies in 149 patients 5 years to 24 years of age [see Adverse Reactions (6.1)].

06/05/2023 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Pain Episodes in Patients with Sickle Cell Disease

Newly added subsection:

In postmarketing reports, acute pain episodes shortly following DEFINITY administration have been reported in patients with sickle cell disease (SCD). The pain episodes included moderate to severe back pain and vaso-occlusive crisis [see Adverse Reactions (6.2)].

If a patient with sickle cell disease experiences new or worsening pain, discontinue DEFINITY.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Pain Episodes in Patients with Sickle Cell Disease [see Warnings and Precautions (5.5)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Blood and Lymphatic System

Acute pain episodes including vaso-occlusive crisis in patients with sickle cell disease

04/09/2021 (SUPPL-25)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

Do not administer DEFINITY to patients with known or suspected:

Hypersensitivity to perflutren lipid microsphere or its components, such as polyethylene glycol (PEG) [see Warnings and Precautions (5 .2) and Description (11)].

5 Warnings and Precautions

5.2 Hypersensitivity Reactions

Additions and/or revisions underlined:

Anaphylaxis, with manifestations that may include death, shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema. These reactions have occurred in patients with no prior exposure to perflutren-containing microsphere products. DEFINITY contains PEG. There may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG see Adverse Reactions (6 .2) and Description (11)]. Clinically assess patients for prior hypersensitivity reactions to products containing PEG, such as certain colonoscopy bowel preparations and laxatives. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for hypersensitivity reactions.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… The following adverse reactions have been identified during the post-marketing use of perflutren and PEG-containing microsphere products …

… These reactions typically occurred within 30 minutes of DEFINITY administration. These serious reactions may be increased among patients with pre-existing PEG hypersensitivity and/or unstable cardiopulmonary conditions …

Reported reactions included:

… Hypersensitivity

Anaphylaxis, with manifestations that may include death, shock, bronchospasm …

04/09/2021 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

Do not administer DEFINITY to patients with known or suspected:

Hypersensitivity to perflutren lipid microsphere or its components, such as polyethylene glycol (PEG) [see Warnings and Precautions (5 .2) and Description (11)].

5 Warnings and Precautions

5.2 Hypersensitivity Reactions

Additions and/or revisions underlined:

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… The following adverse reactions have been identified during the post-marketing use of perflutren and PEG-containing microsphere products …

Reported reactions included:

… Hypersensitivity

Anaphylaxis, with manifestations that may include death, shock, bronchospasm …

11/17/2020 (SUPPL-24)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

Do not administer DEFINITY RT to patients with known or suspected:

Hypersensitivity to perflutren lipid microsphere or its components [see Warnings and Precautions (5) and Description (11)].

5 Warnings and Precautions

RT is added to Definity throughout this section.

Additions and/or revisions underlined:

5.2 Hypersensitivity Reactions

… Shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema have occurred in patients with no prior exposure to perflutren-containing microsphere products, including patients with prior allergic reaction(s) to polyethylene glycol [see Adverse Reactions (6) and Description (11)]. Always have cardiopulmonary …

Other

RT is added to Definity throughout the labeling.

12/12/2018 (SUPPL-22)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; extensive changes. Please refer to label for complete information.

01/19/2017 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypersensitivity Reactions

(Revised subsection title; additions and/or revisions are underlined)

In postmarketing use, serious hypersensitivity reactions were observed during or shortly following perflutren-containing microsphere administration including:

… Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for hypersensitivity reactions.

5.3 Systemic Embolization

(Revised subsection title; additions and/or revisions are underlined)

When administering DEFINITY to patients with a cardiac shunt, the microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following DEFINITY administration. DEFINITY is only for intravenous administration; do not administer DEFINITY by intra-arterial injection.

5.4 Ventricular Arrhythmia Related to High Mechanical Index

(Revised subsection title; additions and/or revisions are underlined)

… DEFINITY is not recommended for use at mechanical indices greater than 0.8.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described elsewhere in the labeling:

x Serious Cardiopulmonary Reactions

x Hypersensitivity Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Fatal cardiopulmonary and hypersensitivity reactions and other serious but non-fatal adverse reactions were uncommonly reported. These reactions typically occurred within 30 minutes of DEFINITY administration. These serious reactions…

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise patients to inform their healthcare provider if they develop any symptoms of hypersensitivity after DEFINITY administration, including rash, wheezing, or shortness of breath.