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.

GADAVIST (NDA-201277)

(GADOBUTROL)

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

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03/05/2025 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Respiratory Distress Syndrome

Newly added subsection:

Acute respiratory distress syndrome (ARDS) has been reported in patients administered GADAVIST and may be characterized by severe hypoxemia requiring oxygen support and mechanical ventilation. These manifestations may resemble an immediate hypersensitivity reaction with onset of respiratory distress within <30 minutes to 24 hours after GADAVIST administration. For patients demonstrating respiratory distress after GADAVIST administration, assess oxygen requirement and monitor for worsening respiratory function.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.4)]
Gadolinium Retention [see Warnings and Precautions (5.5)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following additional adverse reactions have been identified during postmarketing use of Gadavist or other GBCAs. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
…

Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema
…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Respiratory Distress Syndrome

Advise patients that acute respiratory distress syndrome (ARDS) has occurred with GADAVIST. Inform patients on the symptoms of the observed ARDS cases, and instruct patients to inform their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.4)].
…
MEDICATION GUIDE
Additions and/or revisions underlined:
…
What are the possible side effects of Gadavist?

See “What is the most important information I should know about Gadavist?”
Allergic reactions. Gadavist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.
A serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider right away if you have shortness of breath with or without a fever, trouble breathing, or a fast rate of breathing after receiving Gadavist.
…

07/23/2024 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following to the bulleted line listing:

Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration

01/26/2024 (SUPPL-23)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS

Risk Associated with Intrathecal use

Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Gadavist is not approved for intrathecal use [see Warnings and Precautions (5.1)].

…

5 Warnings and Precautions

5.1 Risk Associated with Intrathecal Use

Newly added subsection:

Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of Gadavist have not been established with intrathecal use. Gadavist is not approved for intrathecal use [see Dosage and Administration (2.2)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is the most important information I should know about Gadavist?

GBCAs like Gadavist may cause serious side effects including death, coma, encephalopathy, and seizures when it is given intrathecally (injection given into the spinal canal). It is not known if Gadavist is safe and effective with intrathecal use. Gadavist is not approved for this use.
…

07/12/2019 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

The adverse reactions described in this section reflect Gadavist exposure in 7,713 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 52% of the subjects were male and the ethnic distribution was 62% Caucasian, 28% Asian, 5% Hispanic, 2.5% Black, and 2.5% patients of other ethnic groups.

Following Table 2: Adverse Reactions, addition of ‘hypersensitivity/anaphylactic reaction’ to adverse reactions that occurred with a frequency of <0.1%.

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

… and there is limited GBCA gastrointestinal absorption in the breast-fed infant. Gadobutrol is present in rat milk.

Data

… via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine).

8.4 Pediatric Use

Extensively changed; please refer to label for complete information.

04/26/2018 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Gadolinium Retention

(Newly Added Subsection)

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (for example, brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, gadolinium retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine),MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].

Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention.

While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

General Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.
Skin: Gadolinium associated plaques

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. In animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose.Because of the potential risks of gadolinium to the fetus, use Gadavist only if imaging is essential during pregnancy and cannot be delayed.

Data

Human Data.

Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration.

Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non- contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.

Animal Data

Gadolinium Retention

GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
General Precautions
Gadolinium Retention
• Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs.

Medication Guide

(Newly added Medication Guide; please refer to labeling)